U.S. patent number 8,299,243 [Application Number 13/248,446] was granted by the patent office on 2012-10-30 for indazole, benzisoxazole, and benzisothiazole kinase inhibitors.
This patent grant is currently assigned to AbbVie Inc.. Invention is credited to Yujia Dai, Steven K. Davidsen, Anna M. Ericsson, Kresna Hartandi, Zhiqin Ji, Michael R. Michaelides.
United States Patent |
8,299,243 |
Dai , et al. |
October 30, 2012 |
Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
Abstract
Compounds having the formula ##STR00001## are useful for
inhibiting protein tyrosine kinases. The present invention also
discloses methods of making the compounds, compositions containing
the compounds, and methods of treatment using the compounds.
Inventors: |
Dai; Yujia (Gurnee, IL),
Davidsen; Steven K. (Libertyville, IL), Ericsson; Anna
M. (Shrewsbury, MA), Hartandi; Kresna (Belmont, CA),
Ji; Zhiqin (Libertyville, IL), Michaelides; Michael R.
(Libertyville, IL) |
Assignee: |
AbbVie Inc. (North Chicago,
IL)
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Family
ID: |
34083118 |
Appl.
No.: |
13/248,446 |
Filed: |
September 29, 2011 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20120022253 A1 |
Jan 26, 2012 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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12507575 |
Jul 22, 2009 |
8063091 |
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11867887 |
Oct 6, 2009 |
7598283 |
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10842292 |
Nov 20, 2007 |
7297709 |
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60472810 |
May 22, 2003 |
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Current U.S.
Class: |
544/115;
546/275.7; 548/241; 546/199; 548/362.1 |
Current CPC
Class: |
A61P
35/00 (20180101); A61P 37/06 (20180101); C07D
409/14 (20130101); C07D 409/04 (20130101); C07D
231/56 (20130101); C07D 261/20 (20130101); C07D
403/12 (20130101); C07D 409/12 (20130101); C07D
413/12 (20130101); C07D 401/04 (20130101); C07D
401/10 (20130101); C07D 403/14 (20130101); C07D
409/10 (20130101); C07D 275/04 (20130101); C07D
401/12 (20130101) |
Current International
Class: |
C07D
413/02 (20060101); C07D 261/20 (20060101); C07D
231/56 (20060101); C07D 211/08 (20060101); C07D
401/02 (20060101) |
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|
Primary Examiner: Saeed; Kamal
Attorney, Agent or Firm: Gesicki; Glen J.
Parent Case Text
This application is a divisional of U.S. patent application Ser.
No. 12/507,575, filed Jul. 22, 2009, which is a continuation of
U.S. patent application Ser. No. 11/867, 887, filed Oct. 5, 2007,
now U.S. Pat. No. 7,598,283, which is a divisional of U.S. patent
application Ser. No. 10/842,292, filed May 10, 2004, now U.S. Pat.
No. 7,297,709, which claims priority to U.S. Patent Application No.
60/472,810, filed May 22, 2003, each of which is herein
incorporated by reference.
Claims
The invention claimed is:
1. A compound of formula (I) ##STR00014## or a therapeutically
acceptable salt thereof, wherein A is phenyl; X is NR.sup.9; one of
R.sup.1 and R.sup.2 is hydrogen and the other is selected from the
group consisting of aryloxyalkyl, heterocyclyl,
heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl,
heterocyclyloxyalkyl, (NR.sup.aR.sup.b)alkoxy,
(NR.sup.aR.sup.b)alkenyl, (NR.sup.aR.sup.b)alkyl,
(NR.sup.aR.sup.b)alkynyl, (NR.sup.aR.sup.b)carbonylalkenyl, and
(NR.sup.aR.sup.b)carbonylalkyl; R.sup.3 and R.sup.4 are each
independently selected from the group consisting of hydrogen,
alkoxy, alkoxyalkoxy, alkyl, halo, haloalkoxy, haloalkyl, and
hydroxy; R.sup.5 is LR.sup.6; L is selected from the group
consisting of
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n and
CH.sub.2C(O)NR.sup.7, wherein m is 0 and n is 0, and wherein each
group is drawn with its left end attached to A; R.sup.6 is selected
from the group consisting of hydrogen, aryl, cycloalkyl,
heterocyclyl, and 1,3-benzodioxolyl wherein the 1,3-benzodioxolyl
can be optionally substituted with one, two, or three substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,
arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,
haloalkoxy, haloalkyl, a second heterocyclyl group,
heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d,
and (NR.sup.cR.sup.d)alkyl; R.sup.7 and R.sup.8 are independently
selected from the group consisting of hydrogen and alkyl; R.sup.9
is selected from the group consisting of hydrogen, alkenyl,
alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl,
hydroxyalkyl, and (NR.sup.aR.sup.b)alkyl; R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen,
alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl,
arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl,
heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclylalkyl and
heterocyclyl.
2. The compound of claim 1 of formula (II) ##STR00015## or a
therapeutically acceptable salt thereof, wherein X is NR.sup.9; one
of R.sup.1 and R.sup.2 is hydrogen and the other is selected from
the group consisting of aryloxyalkyl, heterocyclyl,
heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl,
heterocyclyloxyalkyl, (NR.sup.aR.sup.b)alkoxy,
(NR.sup.aR.sup.b)alkenyl, (NR.sup.aR.sup.b)alkyl,
(NR.sup.aR.sup.b)carbonylalkenyl, and
(NR.sup.aR.sup.b)carbonylalkyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy; L is
selected from the group consisting of
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n and
CH.sub.2C(O)NR.sup.7, wherein m is 0 and n is 0, and wherein each
group is drawn with its left end attached to the ring substituted
with R.sup.3 and R.sup.4; R.sup.7 and R.sup.8 are independently
selected from the group consisting of hydrogen and alkyl; R.sup.9
is selected from the group consisting of hydrogen, alkenyl,
alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl,
hydroxyalkyl, and (NR.sup.aR.sup.b)alkyl; R.sup.10 and R.sup.11 are
independently selected from the group consisting of hydrogen,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, and --NR.sup.cR.sup.d; R.sup.a and R.sup.b are independently
selected from the group consisting of hydrogen, alkyl,
alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
heterocyclylsulfonyl; and R.sup.c and R.sup.d are independently
selected from the group consisting of hydrogen, alkyl,
alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, and heterocyclylalkyl.
3. The compound of claim 2 wherein L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n.
4. The compound of claim 3 wherein R.sup.7 and R.sup.8 are
hydrogen, and R.sup.9 is hydrogen.
5. The compound of claim 4 wherein one of R.sup.1 and R.sup.2 is
hydrogen and the other is heterocyclylalkoxy.
6. The compound of claim 5 selected from the group consisting of
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-m-
ethylphenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phen-
ylurea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)--
N'-(3-fluorophenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-(3-br-
omophenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-(3-et-
hylphenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[2-f-
luoro-5-(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[4-f-
luoro-3-(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-(3-ch-
lorophenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(-
trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)--
N'-(3-methylphenyl)urea;
N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)--
N-(3-chlorophenyl)urea;
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2-f-
luoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phe-
nylurea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl-
)-N'-(3-fluorophenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2--
fluoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3--
methylphenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-(3-b-
romophenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[2--
fluoro-5-(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3--
chlorophenyl)urea;
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[3--
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-
-indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-
-indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-
-indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-
-indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethoxy]-1H-
-indazol-4-yl}phenyl)-N'-(3,5-dimethylphenyl)urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl}phenyl)-N'-phen-
y]urea;
N-(4-{3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl}phenyl)--
N'-(3-fluorophenyl)urea;
N-(4-{3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl}phenyl)-N'-(2-f-
luoro-5-methylphenyl)urea;
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3--
methylphenyl)urea;
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[2-f-
luoro-5-(trifluoromethyl)phenyl]urea;
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3--
chlorophenyl)urea;
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[3--
(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-
-fluoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-
-methylphenyl)urea;
N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-
-chlorophenyl)urea;
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3--
bromophenyl)urea;
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}-2-fluo-
rophenyl)-N'-(2-fluoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)-
-N'-(3-methylphenyl)urea;
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)-
-N'-(3-chlorophenyl)urea;
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)-
-N'-(4-fluoro-3-methylphenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chl-
orophenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-met-
hylphenyl)urea;
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[4-flu-
oro-3-(trifluoromethyl)phenyl]urea;
N-{-4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(4-fl-
uoro-3-methylphenyl)urea;
N-{-4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-ch-
loro-4-fluorophenyl)urea;
N-{-4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(t-
rifluoromethyl)phenyl]urea;
N-{-4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fl-
uoro-5-methylphenyl)urea;
N-{-4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-me-
thylphenyl)urea;
N-{-4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-ch-
lorophenyl)urea; and
N-{-4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fl-
uoro-5-methylphenyl)urea.
7. The compound of claim 4 wherein one of R.sup.1 and R.sup.2 is
hydrogen and the other is selected from the group consisting of
aryloxyalkyl, heterocyclyl, heterocyclylalkyl, and
heterocyclyloxyalkyl.
8. The compound of claim 7 selected from the group consisting of
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-(3-fluo-
rophenyl)urea;
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-(3-meth-
ylphenyl)urea;
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-[2-fluo-
ro-5-(trifluoromethyl)phenyl]urea;
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-[4-fluo-
ro-3-(trifluoromethyl)phenyl]urea;
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-[3-(tri-
fluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)--
N'-(3-chlorophenyl)urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)--
N'-(3-methylphenyl)urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)--
N'-(3-fluorophenyl)urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)--
N'-[3-(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)--
N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)--
N'-(2-fluoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(t-
rifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-f-
luoro-5-methylphenyl)urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N-(3-ch-
lorophenyl)urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(-
trifluoromethyl)phenyl]urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-m-
ethylphenyl)urea;
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(4-f-
luoro-3-methylphenyl)urea;
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methy-
lphenyl)urea;
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)u-
rea;
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoro-
methyl)phenyl]urea;
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methy-
lphenyl)urea;
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trif-
luoromethyl)phenyl]urea;
N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl-
)phenyl]urea;
N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylp-
henyl)urea;
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methy-
lphenyl)urea;
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluorometh-
yl)phenyl]urea;
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)u-
rea;
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-m-
ethylphenyl)urea;
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trif-
luoromethyl)phenyl]urea; and
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trif-
luoromethyl)phenyl]urea.
Description
TECHNICAL FIELD
The present invention relates to compounds which are useful for
inhibiting protein tyrosine kinases, methods of making the
compounds, compositions containing the compounds, and methods of
treatment using the compounds.
BACKGROUND OF THE INVENTION
Protein tyrosine kinases (PTKs) are enzymes which catalyse the
phosphorylation of specific tyrosine residues in cellular proteins.
This post-translational modification of these substrate proteins,
often enzymes themselves, acts as a molecular switch regulating
cell proliferation, activation, or differentiation. Aberrant or
excessive PTK activity has been observed in many disease states
including benign and malignant proliferative disorders as well as
diseases resulting from inappropriate activation of the immune
system (e.g., autoimmune disorders), allograft rejection, and graft
vs. host disease. In addition, endothelial-cell specific receptor
PTKs such as KDR and Tie-2 mediate the angiogenic process, and are
thus involved in supporting the progression of cancers and other
diseases involving inappropriate vascularization (e.g., diabetic
retinopathy, choroidal neovascularization due to age-related
macular degeneration, psoriasis, arthritis, retinopathy of
prematurity, and infantile hemangiomas).
The identification of effective small compounds which specifically
inhibit signal transduction and cellular proliferation by
modulating the activity of tyrosine kinases to regulate and
modulate abnormal or inappropriate cell proliferation,
differentiation, or metabolism is therefore desirable. In
particular, the identification of methods and compounds that
specifically inhibit the function of a tyrosine kinase which is
essential for antiogenic processes or the formation of vascular
hyperpermeability leading to edema, ascites, effusions, exudates,
and macromolecular extravasation and matrix deposition as well as
associated disorders would be beneficial.
SUMMARY OF THE INVENTION
In its principle embodiment the present invention provides a
compound of formula (I)
##STR00002## or a therapeutically acceptable salt thereof,
wherein
A is selected from the group consisting of indolyl, phenyl,
pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and thienyl;
X is selected from the group consisting of O, S, and NR.sup.9;
R.sup.1 and R.sup.2 are independently selected from the group
consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl,
aryl, arylalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy,
haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,
heterocyclylalkyl, heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy,
hydroxyalkyl, (NR.sup.aR.sup.b)alkoxy, (NR.sup.aR.sup.b)alkenyl,
(NR.sup.aR.sup.b)alkyl, (NR.sup.aR.sup.b)alkynyl,
(NR.sup.aR.sup.b)carbonylalkenyl, and
(NR.sup.aR.sup.b)carbonylalkyl;
R.sup.3, R.sup.4, and R.sup.5 are each independently selected from
the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl,
halo, haloalkoxy, haloalkyl, hydroxy, and LR.sup.6; provided that
at least two of R.sup.3, R.sup.4, and R.sup.5 are other than
LR.sup.6;
L is selected from the group consisting of
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n and
CH.sub.2C(O)NR.sup.7, wherein m and n are independently 0 or 1, and
wherein each group is drawn with its left end attached to A;
R.sup.6 is selected from the group consisting of hydrogen, aryl,
cycloalkyl, heterocyclyl, and 1,3-benzodioxolyl wherein the
1,3-benzodioxolyl can be optionally substituted with one, two, or
three substituents independently selected from the group consisting
of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy,
cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second
heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.cR.sup.d, and (NR.sup.cR.sup.d)alkyl;
R.sup.7 and R.sup.8 are independently selected from the group
consisting of hydrogen and alkyl;
R.sup.9 is selected from the group consisting of hydrogen, alkenyl,
alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl,
hydroxyalkyl, and (NR.sup.aR.sup.b)alkyl;
R.sup.a and R.sup.b are independently selected from the group
consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,
alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl,
haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and
heterocyclylsulfonyl; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, and
heterocyclylalkyl.
In another embodiment the present invention provides a compound of
formula (II)
##STR00003## or a therapeutically acceptable salt thereof,
wherein
X is selected from the group consisting of O, S, and NR.sup.9;
R.sup.1 and R.sup.2 are independently selected from the group
consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl,
aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl,
heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl,
heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,
(NR.sup.aR.sup.b)alkoxy, (NR.sup.aR.sup.b)alkenyl,
(NR.sup.aR.sup.b)alkyl, (NR.sup.aR.sup.b)carbonylalkenyl, and
(NR.sup.aR.sup.b)carbonylalkyl;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of hydrogen, alkoxy, alkyl, halo, haloalkoxy, haloalkyl,
and hydroxy;
L is selected from the group consisting of
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n and
CH.sub.2C(O)NR.sup.7, wherein m and n are independently 0 or 1, and
wherein each group is drawn with its left end attached to the ring
substituted with R.sup.3 and R.sup.4;
R.sup.7 and R.sup.8 are independently selected from the group
consisting of hydrogen and alkyl;
R.sup.9 is selected from the group consisting of hydrogen, alkenyl,
alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl,
hydroxyalkyl, and (NR.sup.aR.sup.b)alkyl;
R.sup.10 and R.sup.11 are independently selected from the group
consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, nitro, and --NR.sup.cR.sup.d;
R.sup.a and R.sup.b are independently selected from the group
consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl,
arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, and
heterocyclylalkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein X is O and A, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is 1,3-benzodioxolyl optionally substituted with one, two,
or three substituents independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy,
cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second
heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.cR.sup.d, and (NR.sup.cR.sup.d)alkyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and
R.sup.8 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is 1,3-benzodioxolyl optionally substituted with one, two,
or three substituents independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy,
cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second
heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.cR.sup.d, and (NR.sup.cR.sup.d)alkyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; R.sup.3, R.sup.4, R.sup.7,
and R.sup.8 are hydrogen; and R.sup.c and R.sup.d are selected from
the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is 1,3-benzodioxolyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; and R.sup.3, R.sup.4,
R.sup.7, and R.sup.8 are hydrogen.
In another embodiment, the present invention provides a compound of
formula (I) wherein X is S and A, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is 1,3-benzodioxolyl optionally substituted with one, two,
or three substituents independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy,
cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second
heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.cR.sup.d, and (NR.sup.cR.sup.d)alkyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and
R.sup.8 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is 1,3-benzodioxolyl optionally substituted with one, two,
or three substituents independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy,
cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second
heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.cR.sup.d, and (NR.sup.cR.sup.d)alkyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; R.sup.3, R.sup.4, R.sup.7,
and R.sup.8 are hydrogen; and R.sup.c and R.sup.d are selected from
the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is 1,3-benzodioxolyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; and R.sup.3, R.sup.4,
R.sup.7, and R.sup.8 are hydrogen.
In another embodiment, the present invention provides a compound of
formula (I) wherein X is NR.sup.9; and A, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, and R.sup.9 are as defined in formula
(I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is 1,3-benzodioxolyl optionally substituted with
one, two, or three substituents independently selected from the
group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy,
carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second
heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.cR.sup.d, and (NR.sup.cR.sup.d)alkyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7,
R.sup.8, and R.sup.9 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is 1,3-benzodioxolyl optionally substituted with
one, two, or three substituents independently selected from the
group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy,
carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second
heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.cR.sup.d, and (NR.sup.cR.sup.d)alkyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; R.sup.3, R.sup.4, R.sup.7,
and R.sup.8 are hydrogen; R.sup.9 is selected from the group
consisting of hydrogen and alkyl; and R.sup.c and R.sup.d are
selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is 1,3-benzodioxolyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; R.sup.3, R.sup.4, R.sup.7,
and R.sup.8 are hydrogen; and R.sup.9 is selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is cycloalkyl optionally substituted with one, two, or
three substituents independently selected from the group consisting
of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl,
and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d and R.sup.8 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is cycloalkyl wherein the cycloalkyl is selected from the
group consisting of cyclobutyl, cyclopentyl, and cyclohexyl,
wherein the cycloalkyl is optionally substituted with one, two, or
three substituents independently selected from the group consisting
of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl,
and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy, (NR.sup.aR.sup.b)alkoxy, (NR.sup.aR.sup.b)alkyl, and
(NR.sup.aR.sup.b)carbonylalkenyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R.sup.7
and R.sup.8 are hydrogen; R.sup.a and R.sup.b are independently
selected from the group consisting of hydrogen and alkyl; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is cycloalkyl wherein the cycloalkyl is cyclopentyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; and R.sup.3, R.sup.4,
R.sup.7, and R.sup.8 are hydrogen.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is cycloalkyl optionally substituted with one, two, or
three substituents independently selected from the group consisting
of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, (NR.sup.cR.sup.d)alkyl, and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and
R.sup.8 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is cycloalkyl wherein the cycloalkyl is selected from the
group consisting of cyclobutyl, cyclopentyl, and cyclohexyl,
wherein the cycloalkyl is optionally substituted with one, two, or
three substituents independently selected from the group consisting
of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl,
and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy, (NR.sup.aR.sup.b)alkoxy, (NR.sup.aR.sup.b)alkyl, and
(NR.sup.aR.sup.b)carbonylalkenyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R.sup.7
and R.sup.8 are hydrogen; R.sup.a and R.sup.b are independently
selected from the group consisting of hydrogen and alkyl; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is cycloalkyl wherein the cycloalkyl is cyclopentyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; and R.sup.3, R.sup.4,
R.sup.7, and R.sup.8 are hydrogen.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is cycloalkyl optionally substituted with one,
two, or three substituents independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl,
and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7,
R.sup.8, and R.sup.9 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is cycloalkyl wherein the cycloalkyl is selected
from the group consisting of cyclobutyl, cyclopentyl, and
cyclohexyl, wherein the cycloalkyl is optionally substituted with
one, two, or three substituents independently selected from the
group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl,
and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy, (NR.sup.aR.sup.b)alkoxy, (NR.sup.aR.sup.b)alkyl, and
(NR.sup.aR.sup.b)carbonylalkenyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R.sup.7
and R.sup.8 are hydrogen; R.sup.9 is selected from the group
consisting of hydrogen and alkyl; R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen and
alkyl; and R.sup.c and R.sup.d are independently selected from the
group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is cycloalkyl wherein the cycloalkyl is
cyclopentyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; R.sup.3, R.sup.4, R.sup.7,
and R.sup.8 are hydrogen; and R.sup.9 is selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is heterocyclyl optionally substituted with one, two, or
three substituents independently selected from the group consisting
of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl,
and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and
R.sup.8 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is heterocyclyl wherein the heterocyclyl is selected from
the group consisting of furyl, isoxazolyl, isothiazolyl, oxazolyl,
pyridinyl, thiazolyl, and thienyl, wherein the heterocyclyl is
optionally substituted with one, two, or three substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
--NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl, and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy, (NR.sup.aR.sup.b)alkoxy, (NR.sup.aR.sup.b)alkyl, and
(NR.sup.aR.sup.b)carbonylalkenyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R.sup.7
and R.sup.8 are hydrogen; R.sup.a and R.sup.b are independently
selected from the group consisting of hydrogen and alkyl; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is O; R.sup.5 is LR.sup.6;
R.sup.6 is heterocyclyl wherein the heterocyclyl is thienyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; and R.sup.3, R.sup.4,
R.sup.7, and R.sup.8 are hydrogen.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is heterocyclyl optionally substituted with one, two, or
three substituents independently selected from the group consisting
of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl,
and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and
R.sup.8 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is heterocyclyl wherein the heterocyclyl is selected from
the group consisting of furyl, isoxazolyl, isothiazolyl, oxazolyl,
pyridinyl, thiazolyl, and thienyl, wherein the heterocyclyl is
optionally substituted with one, two, or three substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
--NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl, and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy, (NR.sup.aR.sup.b)alkoxy, (NR.sup.aR.sup.b)alkyl, and
(NR.sup.aR.sup.b)carbonylalkenyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R.sup.7
and R.sup.8 are hydrogen; R.sup.a and R.sup.b are independently
selected from the group consisting of hydrogen and alkyl; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is S; R.sup.5 is LR.sup.6;
R.sup.6 is heteocyclyl wherein the heterocyclyl is thienyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; and R.sup.3, R.sup.4,
R.sup.7, and R.sup.8 are hydrogen.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is heterocyclyl optionally substituted with one,
two, or three substituents independently selected from the group
consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,
alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl,
and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.c, R.sup.d, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7,
R.sup.8, and R.sup.9 are as defined in formula (I).
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is heterocyclyl wherein the heterocyclyl is
selected from the group consisting of furyl, isoxazolyl,
isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl, wherein
the heterocyclyl is optionally substituted with one, two, or three
substituents independently selected from the group consisting of
alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
--NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl, and oxo; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo,
hydroxy, (NR.sup.aR.sup.b)alkoxy, (NR.sup.aR.sup.b)alkyl, and
(NR.sup.aR.sup.b)carbonylalkenyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkyl, alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R.sup.7
and R.sup.8 are hydrogen; R.sup.9 is selected from the group
consisting of hydrogen and alkyl; R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen and
alkyl; and R.sup.c and R.sup.d are independently selected from the
group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (I) wherein A is phenyl; X is NR.sup.9; R.sup.5 is
LR.sup.6; R.sup.6 is heterocyclyl wherein the heterocyclyl is
thienyl; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 and R.sup.2 are independently selected from the
group consisting of hydrogen and alkoxy; R.sup.3, R.sup.4, R.sup.7,
and R.sup.8 are hydrogen; and R.sup.9 is selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of formula (I), or
a therapeutically acceptable salt thereof, in combination with a
therapeutically acceptable carrier.
In another embodiment, the present invention provides a method for
inhibiting protein kinase in a patient in recognized need of such
treatment comprising administering to the patient a therapeutically
acceptable amount of a compound of formula (I), or a
therapeutically acceptable salt thereof.
In another embodiment, the present invention provides a method for
treating cancer in a patient in recognized need of such treatment
comprising administering to the patient a therapeutically
acceptable amount of a compound of formula (I), or a
therapeutically acceptable salt thereof.
In another embodiment, the present invention provides a compound of
formula (II) wherein L is CH.sub.2C(O)NR.sup.7; and X, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.10, and R.sup.11 are as
defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is CH.sub.2C(O)NR.sup.7; and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.9, R.sup.10, and
are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is CH.sub.2C(O)NR.sup.7; and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.9, R.sup.10, and
R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is CH.sub.2C(O)NR.sup.7;
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.7 are hydrogen;
R.sup.9 is selected from the group consisting of hydrogen and
alkyl; R.sup.10 and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is CH.sub.2C(O)NR.sup.7;
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.7 are hydrogen;
R.sup.9 is selected from the group consisting of hydrogen and
alkyl; R.sup.10 and R.sup.11 independently selected from the group
consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,
--NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is phenoxy; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is CH.sub.2C(O)NR.sup.7;
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.7 are hydrogen;
R.sup.9 is selected from the group consisting of hydrogen and
alkyl; R.sup.10 and R.sup.11 independently selected from the group
consisting of hydrogen, alkyl, halo, and haloalkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8, R.sup.10,
and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; and L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.9, R.sup.10, and R.sup.11 are as defined in
formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is selected from
the group consisting of alkoxyalkyl, alkyl, alkylcarbonyl, aryl,
heterocyclylalkyl, hydroxyalkyl, and (NR.sup.aR.sup.b)alkyl; and
R.sup.a, R.sup.b, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.10, and
R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.10, and R.sup.11 are as
defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is selected from the group consisting of
hydrogen and halo and the other is selected from the group
consisting of hydroxy, hydroxyalkyl, and (NR.sup.aR.sup.b)alkyl;
and R.sup.a, R.sup.b, R.sup.3, R.sup.4, R.sup.10, and R.sup.11 are
as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is selected from the group consisting of
hydrogen and halo and the other is selected from the group
consisting of hydroxy, hydroxyalkyl, and (NR.sup.aR.sup.b)alkyl;
one of R.sup.3 and R.sup.4 is hydrogen and the other is selected
from the group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy,
and hydroxy; R.sup.10 and R.sup.11 are independently selected from
the group consisting of hydrogen, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and
--NR.sup.cR.sup.d; R.sup.a and R.sup.b are independently selected
from the group consisting of hydrogen and alkyl; and R.sup.c and
R.sup.d are independently selected from the group consisting of
hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.7, R.sup.8, and R.sup.9 are
hydrogen; R.sup.4 is selected from the group consisting of hydrogen
and halo; R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, nitro, and --NR.sup.cR.sup.d; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8,
R.sup.9 are hydrogen; R.sup.4 is selected from the group consisting
of hydrogen and halo; R.sup.10 and R.sup.11 are independently
selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d, and aryloxy
wherein the aryloxy is phenoxy; and R.sup.c and R.sup.d are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.7, R.sup.8, and R.sup.9 are
hydrogen; R.sup.4 is selected from the group consisting of hydrogen
and halo; and R.sup.10 and R.sup.11 are independently selected from
the group consisting of hydrogen, alkyl, halo, and haloalkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.7, and R.sup.8 are
hydrogen; R.sup.9 is alkyl; R.sup.4 is selected from the group
consisting of hydrogen and halo; R.sup.10 and R.sup.11 are
independently selected from the group consisting of hydrogen,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, and --NR.sup.cR.sup.d; and R.sup.c and R.sup.d are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.7, and R.sup.8 are
hydrogen; R.sup.9 is alkyl; R.sup.4 is selected from the group
consisting of hydrogen and halo; R.sup.10 and R.sup.11 are
independently selected from the group consisting of hydrogen,
alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d, and
aryloxy wherein the aryloxy is phenoxy; and R.sup.c and R.sup.d are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.7, and R.sup.8 are
hydrogen; R.sup.9 is alkyl; R.sup.4 is selected from the group
consisting of hydrogen and halo; and R.sup.10 and R.sup.11 are
independently selected from the group consisting of hydrogen,
alkyl, halo, and haloalkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is halo; and
R.sup.3, R.sup.4, R.sup.10, and R.sup.11 are as defined in formula
(II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is halo; R.sup.3
and R.sup.4 are independently selected from the group consisting of
hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy;
R.sup.10 and R.sup.11 are selected from the group consisting of
hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,
--NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is phenoxy; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9, L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n, m and n
are 0, R.sup.7 and R.sup.8 are hydrogen, R.sup.9 is hydrogen, one
of R.sup.1 and R.sup.2 is hydrogen and the other is
heterocyclylalkoxy; and R.sup.3, R.sup.4, R.sup.10, and R.sup.11
are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9, L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n, m and n
are 0, R.sup.7 and R.sup.8 are hydrogen, R.sup.9 is hydrogen, one
of R.sup.1 and R.sup.2 is hydrogen and the other is
heterocyclylalkoxy; R.sup.3 and R.sup.4 are independently selected
from the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo,
haloalkoxy, and hydroxy; R.sup.10 and R.sup.11 are selected from
the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is
phenoxy; and R.sup.c and R.sup.d are independently selected from
the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9, L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n, m and n
are 0, R.sup.7 and R.sup.8 are hydrogen, R.sup.9 is hydrogen, one
of R.sup.1 and R.sup.2 is hydrogen and the other is
heterocyclylalkoxy wherein the heterocyclyl is selected from the
group consisting of morpholinyl, piperidinyl, pyridinyl, pyrrolyl,
pyrrolidinyl optionally substituted with oxo, and
3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R.sup.10 and
R.sup.11 are selected from the group consisting of hydrogen,
alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d, and
aryloxy wherein the aryloxy is phenoxy; and R.sup.c and R.sup.d are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is selected from
the group consisting of (NR.sup.aR.sup.b)carbonylalkenyl and
(NR.sup.aR.sup.b)alkoxy; and R.sup.a, R.sup.b, R.sup.3, R.sup.4,
R.sup.10, and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is selected from
the group consisting of (NR.sup.aR.sup.b)carbonylalkenyl and
(NR.sup.aR.sup.b)alkoxy; R.sup.3 and R.sup.4 are independently
selected from the group consisting of hydrogen, alkoxyalkoxy,
alkyl, halo, haloalkoxy, and hydroxy; R.sup.10 and R.sup.11 are
selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d, and aryloxy
wherein the aryloxy is phenoxy; R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen,
alkyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
heterocyclylsulfonyl; and R.sup.c and R.sup.d are independently
selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is selected from
the group consisting of (NR.sup.aR.sup.b)carbonylalkenyl and
(NR.sup.aR.sup.b)alkoxy; R.sup.3 and R.sup.4 are independently
selected from the group consisting of hydrogen, alkoxyalkoxy,
alkyl, halo, haloalkoxy, and hydroxy; R.sup.10 and R.sup.11 are
selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d, and aryloxy
wherein the aryloxy is phenoxy; R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen,
alkyl, alkylsulfonyl, arylsulfonyl wherein the aryl is phenyl,
haloalkylsulfonyl, and heterocyclylsulfonyl wherein the
heterocyclyl is thienyl; and R.sup.c and R.sup.d are independently
selected from the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is selected from
the group consisting of aryloxyalkyl, heterocyclyl,
heterocyclylalkyl and heterocyclyloxyalkyl; and R.sup.3, R.sup.4,
R.sup.10, and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is selected from
the group consisting of aryloxyalkyl, heterocyclyl,
heterocyclylalkyl and heterocyclyloxyalkyl; R.sup.3 and R.sup.4 are
independently selected from the group consisting of hydrogen,
alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R.sup.10 and
R.sup.11 are selected from the group consisting of hydrogen,
alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d, and
aryloxy wherein the aryloxy is phenoxy; and R.sup.c and R.sup.d are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is aryloxyalkyl
wherein the aryl is phenyl optionally substituted with halo;
R.sup.3 and R.sup.4 are independently selected from the group
consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and
hydroxy; R.sup.10 and R.sup.11 are selected from the group
consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,
--NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is phenoxy; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is heterocyclyl
wherein the heterocyclyl is selected from the group consisting of
pyridinyl and thienyl; R.sup.3 and R.sup.4 are independently
selected from the group consisting of hydrogen, alkoxyalkoxy,
alkyl, halo, haloalkoxy, and hydroxy; R.sup.10 and R.sup.11 are
selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d, and aryloxy
wherein the aryloxy is phenoxy; and R.sup.c and R.sup.d are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is
heterocyclylalkyl wherein the heterocyclyl is selected from the
group consisting of morpholinyl and piperazinyl wherein the
piperazinyl is optionally substituted with alkyl; R.sup.3 and
R.sup.4 are independently selected from the group consisting of
hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy;
R.sup.10 and R.sup.11 are selected from the group consisting of
hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,
--NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is phenoxy; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is
heterocyclyloxyalkyl wherein the heterocyclyl is pyridinyl; R.sup.3
and R.sup.4 are independently selected from the group consisting of
hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy;
R.sup.10 and R.sup.11 are selected from the group consisting of
hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,
--NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is phenoxy; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is selected from
the group consisting of alkoxy, alkoxyalkoxy, and alkyl; and
R.sup.3, R.sup.4, R.sup.10, and R.sup.11 are as defined in formula
(II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; one
of R.sup.1 and R.sup.2 is hydrogen and the other is selected from
the group consisting of alkoxy, alkoxyalkoxy, and alkyl; R.sup.3
and R.sup.4 are independently selected from the group consisting of
hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy;
R.sup.10 and R.sup.11 are selected from the group consisting of
hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,
--NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is phenoxy; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n are 0;
R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen; R.sup.1 and
R.sup.2 are hydrogen; and R.sup.3, R.sup.4, R.sup.10, and R.sup.11
as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen;
R.sup.1 and R.sup.2 are hydrogen; one of R.sup.3 and R.sup.4 is
hydrogen and the other is selected from the group consisting of
alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; and R.sup.10
and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen;
R.sup.1 and R.sup.2 are hydrogen; one of R.sup.3 and R.sup.4 is
hydrogen and the other is selected from the group consisting of
alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; and R.sup.10
and R.sup.11 are selected from the group consisting of hydrogen,
alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d, and
aryloxy wherein the aryloxy is phenoxy; and R.sup.c and R.sup.d are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen;
R.sup.1 and R.sup.2 are hydrogen; R.sup.3 and R.sup.4 are hydrogen;
and R.sup.10 and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen;
R.sup.1 and R.sup.2 are hydrogen; R.sup.3 and R.sup.4 are hydrogen;
and R.sup.10 and R.sup.11 are selected from the group consisting of
hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,
--NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is phenoxy; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is NR.sup.9; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.7 and R.sup.8 are hydrogen; R.sup.9 is hydrogen;
R.sup.1 and R.sup.2 are hydrogen; R.sup.3 and R.sup.4 are alkyl;
and R.sup.10 and R.sup.11 are selected from the group consisting of
hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo,
haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,
--NR.sup.cR.sup.d, and aryloxy wherein the aryloxy is phenoxy; and
R.sup.c and R.sup.d are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein R.sup.1 and R.sup.2 are independently selected
from the group consisting of hydrogen, alkoxy, alkoxyalkoxy,
alkoxyalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR.sup.aR.sup.b)alkoxy,
(NR.sup.aR.sup.b)alkenyl, (NR.sup.aR.sup.b)alkyl,
(NR.sup.aR.sup.b)carbonylalkenyl, and
(NR.sup.aR.sup.b)carbonylalkyl; and X, L, R.sup.a, R.sup.b,
R.sup.3, R.sup.4, R.sup.10, and R.sup.11 are as defined in formula
(II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is O and L, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.10, and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is O; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8, R.sup.10, and
R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is O; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and R.sup.8 are
hydrogen; R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, nitro, and --NR.sup.aR.sup.b; and
R.sup.a and R.sup.b are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is O; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and R.sup.8 are
hydrogen; R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.aR.sup.b, and aryloxy wherein the aryloxy is
phenoxy; and R.sup.a and R.sup.b are independently selected from
the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is O; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 is heterocyclylalkoxy; R.sup.2, R.sup.3, R.sup.4,
R.sup.7, and R.sup.8 are hydrogen; R.sup.10 and R.sup.11 are
independently selected from the group consisting of hydrogen,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, and --NR.sup.aR.sup.b; and R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is O; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 is heterocyclylalkoxy wherein the heterocyclyl is
morpholinyl; R.sup.2, R.sup.3, R.sup.4, R.sup.7, and R.sup.8 are
hydrogen; R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.aR.sup.b, and aryloxy wherein the aryloxy is
phenoxy; and R.sup.a and R.sup.b are independently selected from
the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is O; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 is selected from the group consisting of alkoxy,
alkyl, halo, and haloalkoxy; R.sup.2, R.sup.3, R.sup.4, R.sup.7,
and R.sup.8 are hydrogen; R.sup.10 and R.sup.11 are independently
selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, nitro, --NR.sup.aR.sup.b, and aryloxy
wherein the aryloxy is phenoxy; and R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is S and L, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.10, and R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is S; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; and m, n,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, R.sup.8, R.sup.10, and
R.sup.11 are as defined in formula (II).
In another embodiment, the present invention provides a compound of
formula (II) wherein X is S; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and R.sup.8 are
hydrogen; R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl,
alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy,
haloalkyl, hydroxy, hydroxyalkyl, nitro, and --NR.sup.aR.sup.b; and
R.sup.a and R.sup.b are independently selected from the group
consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is S; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and R.sup.8 are
hydrogen; R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.aR.sup.b, and aryloxy wherein the aryloxy is
phenoxy; and R.sup.a and R.sup.b are independently selected from
the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II), wherein X is S; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.7, and R.sup.8 are
hydrogen; and R.sup.10 and R.sup.11 are independently selected from
the group consisting of hydrogen, alkyl, halo, and haloalkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is S; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 is heterocyclylalkoxy; R.sup.2, R.sup.3, R.sup.4,
R.sup.7, and R.sup.8 are hydrogen; R.sup.10 and R.sup.11 are
independently selected from the group consisting of hydrogen,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, and --NR.sup.aR.sup.b; and R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is S; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 is heterocyclylalkoxy wherein the heterocyclyl is
morpholinyl; R.sup.2, R.sup.3, R.sup.4, R.sup.7, and R.sup.8 are
hydrogen; R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl,
carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
nitro, --NR.sup.aR.sup.b, and aryloxy wherein the aryloxy is
phenoxy; and R.sup.a and R.sup.b are independently selected from
the group consisting of hydrogen and alkyl.
In another embodiment, the present invention provides a compound of
formula (II) wherein X is S; L is
(CH.sub.2).sub.mN(R.sup.7)C(O)N(R.sup.8)(CH.sub.2).sub.n; m and n
are 0; R.sup.1 is selected from the group consisting of alkoxy,
alkyl, halo, and haloalkoxy; R.sup.2, R.sup.3, R.sup.4, R.sup.7,
and R.sup.8 are hydrogen; R.sup.10 and R.sup.11 are independently
selected from the group consisting of hydrogen, alkoxy,
alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, nitro, --NR.sup.aR.sup.b, and aryloxy
wherein the aryloxy is phenoxy; and R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen and
alkyl.
In another embodiment, the present invention provides a
pharmaceutical composition comprising a compound of formula (II),
or a therapeutically acceptable salt thereof, in combination with a
therapeutically acceptable carrier.
In another embodiment, the present invention provides a method for
inhibiting protein kinase in a patient in recognized need of such
treatment comprising administering to the patient a therapeutically
acceptable amount of a compound of formula (II), or a
therapeutically acceptable salt thereof.
In another embodiment, the present invention provides a method for
treating cancer in a patient in recognized need of such treatment
comprising administering to the patient a therapeutically
acceptable amount of a compound of formula (II), or a
therapeutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
All publications, issued patents, and patent applications cited
herein are hereby incorporated by reference.
As used herein, the singular forms "a", "an", and "the" include
plural reference unless the context clearly dictates otherwise.
As used in the present specification the following terms have the
meanings indicated:
The term "alkenyl," as used herein, refers to a straight or
branched chain group of one to six carbon atoms containing at least
one carbon-carbon double bond.
The term "alkoxy," as used herein, refers to an alkyl group
attached to the parent molecular moiety through an oxygen atom.
The term "alkoxyalkoxy," as used herein, refers to an alkoxy group
attached to the parent molecular moiety through another alkoxy
group.
The term "alkoxyalkyl," as used herein, refers to an alkyl group
substituted with at least one alkoxy group.
The term "alkoxycarbonyl," as used herein, refers to an alkoxy
group attached to the parent molecular moiety through a carbonyl
group.
The term "alkyl," as used herein, refers to a group derived from a
straight or branched chain saturated hydrocarbon of one to six
carbon atoms. Preferred alkyl groups of the present invention are
of one to three carbon atoms. Most preferred alkyl groups are
methyl and ethyl.
The term "alkylcarbonyl," as used herein, refers to an alkyl group
attached to the parent molecular moiety through a carbonyl
group.
The term "alkylsulfonyl," as used herein, refers to an alkyl group
attached to the parent molecular moiety through a sulfonyl
group.
The term "aryl," as used herein, refers to a phenyl group, or a
bicyclic or tricyclic fused ring system wherein one or more of the
fused rings is a phenyl group. Bicyclic fused ring systems are
exemplified by a phenyl group fused to a monocyclic cycloalkenyl
group, as defined herein, a monocyclic cycloalkyl group, as defined
herein, or another phenyl group. Tricyclic fused ring systems are
exemplified by a bicyclic fused ring system fused to a monocyclic
cycloalkenyl group, as defined herein, a monocyclic cycloalkyl
group, as defined herein, or another phenyl group. Aryl groups
include, but are not limited to, anthracenyl, azulenyl, fluorenyl,
indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The
aryl groups of the present invention can be optionally substituted
with one, two, three, four, or five substituents independently
selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group,
arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,
haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy,
hydroxyalkyl, nitro, --NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl, and
oxo; wherein the second aryl group, the aryl part of the
arylalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and
the heterocyclyl part of the heterocyclylalkyl can be further
optionally substituted with one, two, three, four, or five groups
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl,
hydroxy, hydroxyalkyl, nitro, and oxo.
The term "arylalkyl," as used herein, refers to an alkyl group
substituted with at least one aryl group.
The term "arylcarbonyl," as used herein, refers to an aryl group
attached to the parent molecular moiety through a carbonyl
group.
The term "arylalkoxy," as used herein, refers to an aryl group
attached to the parent molecular moiety through an alkoxy
group.
The term "aryloxy," as used herein, refers to an aryl group
attached to the parent molecular moiety through an oxygen atom.
The term "aryloxyalkyl," as used herein, refers to an aryloxy group
attached to the parent molecular moiety through an alkyl group.
The term "arylsulfonyl," as used herein, refers to an aryl group
attached to the parent molecular moiety through a sulfonyl
group.
The term "carbonyl," as used herein, refers to --C(O)--.
The term "carboxy," as used herein, refers to --CO.sub.2H.
The term "cyano," as used herein, refers to --CN.
The term "cycloalkenyl," as used herein, refers to a non-aromatic
cyclic or bicyclic ring system having three to ten carbon atoms and
one to three rings, wherein each five-membered ring has one double
bond, each six-membered ring has one or two double bonds, each
seven- and eight-membered ring has one to three double bonds, and
each nine- to ten-membered ring has one to four double bonds.
Examples of cycloalkenyl groups include, but are not limited to,
cyclohexenyl, octahydronaphthalenyl, and norbornylenyl.
The term "cycloalkyl," as used herein, refers to a saturated
monocyclic, bicyclic, or tricyclic hydrocarbon ring system having
three to twelve carbon atoms. Examples of cycloalkyl groups
include, but are not limited to, cyclopropyl, cyclopentyl,
cyclohexyl, bicyclo[3.1.1]heptyl, and adamantyl.
The cycloalkyl groups of the present invention can be optionally
substituted with one, two, three, four, or five substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy,
cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,
--NR.sup.cR.sup.d, (NR.sup.cR.sup.d)alkyl, and oxo.
The terms "halo," and "halogen," as used herein, refer to F, Cl,
Br, and I.
The term "haloalkoxy," as used herein, refers to a haloalkyl group
attached to the parent molecular moiety through an oxygen atom.
The term "haloalkyl," as used herein, refers to an alkyl group
substituted by one, two, three, or four halogen atoms.
The term "haloalkylsulfonyl," as used herein, refers to a haloalkyl
group attached to the parent molecular moiety through a sulfonyl
group.
The term "heterocyclyl," as used herein, represents a monocyclic,
bicyclic, or tricyclic ring system wherein one or more rings is a
four-, five-, six-, or seven-membered ring containing one, two, or
three heteroatoms independently selected from the group consisting
of nitrogen, oxygen, and sulfur. Monocyclic ring systems are
exemplified by any 3- or 4-membered ring containing a heteroatom
independently selected from the group consisting of oxygen,
nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one,
two or three heteroatoms wherein the heteroatoms are independently
selected from the group consisting of nitrogen, oxygen and sulfur.
The 3- and 4-membered rings have no double bonds, the 5-membered
ring has from 0-2 double bonds and the 6- and 7-membered rings have
from 0-3 double bonds. Representative examples of monocyclic ring
systems include, but are not limited to, azetidine, azepine,
aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan,
imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline,
isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine,
oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline,
oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole,
pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine,
pyrrole, pyrroline, pyrrolidine, tetrahydrofuran,
tetrahydrothiophene, tetrazine, tetrazole, thiadiazole,
thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine,
thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran,
triazine, triazole, and trithiane. Bicyclic ring systems are
exemplified by any of the above monocyclic ring systems fused to
phenyl ring, a monocyclic cycloalkyl group as defined herein, a
monocyclic cycloalkenyl group, as defined herein, or another
monocyclic heterocyclyl ring system. Representative examples of
bicyclic ring systems include but are not limited to,
benzimidazole, benzothiazole, benzothiophene, benzoxazole,
benzofuran, benzopyran, benzothiopyran, benzodioxine,
1,3-benzodioxole, cinnoline, dihydrobenzimidazole, indazole,
indole, indoline, indolizine, naphthyridine, isobenzofuran,
isobenzothiophene, isoindole, isoindoline, isoquinoline,
phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline,
quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, and
thiopyranopyridine. Tricyclic rings systems are exemplified by any
of the above bicyclic ring systems fused to a phenyl ring, a
monocyclic cycloalkyl group as defined herein, a monocyclic
cycloalkenyl group as defined herein, or another monocyclic
heterocyclyl ring system. Representative examples of tricyclic ring
systems include, but are not limited to, acridine, carbazole,
carboline, dibenzofuran, dibenzothiophene, naphthofuran,
naphthothiophene, oxanthrene, phenazine, phenoxathiin, phenoxazine,
phenothiazine, thianthrene, thioxanthene, and xanthene.
Heterocyclyl groups can be attached to the parent molecular moiety
through a carbon atom or a nitrogen atom in the group.
The heterocyclyl groups of the present invention can be optionally
substituted with one, two, three, four, or five substituents
independently selected from the group consisting of alkenyl,
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,
arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,
haloalkoxy, haloalkyl, a second heterocyclyl group,
heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, --NR.sup.cR.sup.d,
(NR.sup.cR.sup.d)alkyl, and oxo; wherein the aryl, the aryl part of
the arylalkoxy, the arylalkyl, and the aryloxy, the second
heterocyclyl group, and the heterocyclyl part of the
heterocyclylalkyl can be further optionally substituted with one,
two, three, four, or five groups independently selected from the
group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano,
halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and
oxo.
The term "heterocyclylalkenyl," as used herein, refers to an
alkenyl group substituted with at least one heterocyclyl group.
The term "heterocyclylalkoxy," as used herein, refers to a
heterocyclyl group attached to the parent molecular moiety through
an alkoxy group.
The term "heterocyclylalkyl," as used herein, refers to an alkyl
group substituted with at least one heterocyclyl group.
The term "heterocyclyloxy," as used herein, refers to a
heterocyclyl group attached to the parent molecular moiety through
an oxygen atom.
The term "heterocyclyloxyalkyl," as used herein, refers to an alkyl
group substituted with at least one heterocyclyloxy group.
The term "heterocyclylsulfonyl," as used herein, refers to a
heterocyclyl group attached to the parent molecular moiety through
a sulfonyl group.
The term "hydroxy," as used herein, refers to --OH.
The term "hydroxyalkoxy," as used herein, refers to a hydroxy group
attached to the parent molecular moiety through an alkoxy
group.
The term "hydroxyalkyl," as used herein, refers to an alkyl group
substituted with at least one hydroxy group.
The term "nitro," as used herein, refers to --NO.sub.2.
The term "--NR.sup.aR.sup.b," as used herein, represents two
groups, R.sup.a and R.sup.b, which are attached to the parent
molecular moiety through a nitrogen atom. R.sup.a and R.sup.b are
independently selected from the group consisting of hydrogen,
alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl,
arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl,
heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl, wherein
the aryl, the aryl part of the arylalkyl and the arylcarbonyl, the
heterocyclyl, the heterocyclyl part of the heterocyclylalkyl and
the heterocyclylsulfonyl can be further optionally substituted with
one, two, three, four, or five substituents independently selected
from the group consisting of alkenyl, alkoxy, alkyl, cyano, halo,
haloalkyl, haloalkoxy, nitro, and oxo.
The term "(NR.sup.aR.sup.b)alkenyl," as used herein, represents an
alkenyl group substituted with at least one --NR.sup.aR.sup.b
group.
The term "(NR.sup.aR.sup.b)alkoxy," as used herein, represents an
--NR.sup.aR.sup.b group attached to the parent molecular moiety
through an alkoxy group.
The term "(NR.sup.aR.sup.b)alkyl," as used herein, represents an
alkyl group substituted with at least one --NR.sup.aR.sup.b
group.
The term "(NR.sup.aR.sup.b)alkynyl," as used herein, represents an
alkynyl group substituted with at least one --NR.sup.aR.sup.b
group.
The term "(NR.sup.aR.sup.b)carbonyl," as used herein, represents an
(NR.sup.aR.sup.b) group attached to the parent molecular moiety
through a carbonyl group.
The term "(NR.sup.aR.sup.b)carbonylalkenyl," as used herein,
represents an alkenyl group substituted with at least one
(NR.sup.aR.sup.b)carbonyl group.
The term "(NR.sup.aR.sup.b)carbonylalkyl," as used herein,
represents an alkyl group substituted with at least one
(NR.sup.aR.sup.b)carbonyl group.
The term "--NR.sup.cR.sup.d," as used herein, represents two
groups, R.sup.c and R.sup.d, which are attached to the parent
molecular moiety through a nitrogen atom. R.sup.c and R.sup.d are
independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,
heterocyclyl, and heterocyclylalkyl, wherein the aryl, the aryl
part of the arylalkyl, the heterocyclyl, and the heterocyclyl part
of the heterocyclylalkyl can be further optionally substituted with
one, two, three, four, or five substituents independently selected
from the group consisting of alkenyl, alkoxy, alkyl, cyano, halo,
haloalkyl, haloalkoxy, nitro, and oxo.
The term "(NR.sup.cR.sup.d)alkyl," as used herein, represents an
alkyl group substituted with at least one --NR.sup.cR.sup.d
group.
The term "oxo," as used herein, refers to .dbd.O.
The term "sulfonyl," as used herein, refers to --SO.sub.2.
The compounds of the present invention can exist as therapeutically
acceptable salts. The term "therapeutically acceptable salt," as
used herein, represents salts or zwitterionic forms of the
compounds of the present invention which are water or oil-soluble
or dispersible, which are suitable for treatment of diseases
without undue toxicity, irritation, and allergic response; which
are commensurate with a reasonable benefit/risk ratio, and which
are effective for their intended use. The salts can be prepared
during the final isolation and purification of the compounds or
separately by reacting an --NR.sup.aR.sup.b group with a suitable
acid. Representative acid addition salts include acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, formate,
fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate,
methanesulfonate, naphthylenesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylproprionate, picrate, pivalate, propionate, succinate,
tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate,
bicarbonate, para-toluenesulfonate, and undecanoate. Also,
--NR.sup.aR.sup.b groups in the compounds of the present invention
can be quaternized with methyl, ethyl, propyl, and butyl chlorides,
bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl
sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides,
and iodides; and benzyl and phenethyl bromides. Examples of acids
which can be employed to form therapeutically acceptable addition
salts include inorganic acids such as hydrochloric, hydrobromic,
sulfuric, and phosphoric, and organic acids such as oxalic, maleic,
succinic, and citric.
The present compounds can also exist as therapeutically acceptable
prodrugs. The term "therapeutically acceptable prodrug," refers to
those prodrugs or zwitterions which are suitable for use in contact
with the tissues of patients without undue toxicity, irritation,
and allergic response, are commensurate with a reasonable
benefit/risk ratio, and are effective for their intended use. The
term "prodrug," refers to compounds which are rapidly transformed
in vivo to parent compounds of formula (I) or (II) for example, by
hydrolysis in blood.
When it is possible that, for use in therapy, therapeutically
effective amounts of a compound of formula (I) or (II), as well as
therapeutically acceptable salts thereof, may be administered as
the raw chemical, it is possible to present the active ingredient
as a pharmaceutical composition. Accordingly, the invention further
provides pharmaceutical compositions, which include therapeutically
effective amounts of compounds of formula (I) or (II), or
therapeutically acceptable salts thereof, and one or more
pharmaceutically acceptable carriers, diluents, or excipients. The
compounds of formula (I) and (II) and therapeutically acceptable
salts thereof are as described above. The carrier(s), diluent(s),
or excipient(s) must be acceptable in the sense of being compatible
with the other ingredients of the formulation and not deleterious
to the recipient thereof. In accordance with another aspect of the
invention there is also provided a process for the preparation of a
pharmaceutical formulation including admixing a compound of formula
(I) or (II), or a therapeutically acceptable salt thereof, with one
or more pharmaceutically acceptable carriers, diluents, or
excipients.
Pharmaceutical formulations may be presented in unit dose forms
containing a predetermined amount of active ingredient per unit
dose. Such a unit may contain, for example, 0.5 mg to 1 g;
preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a
compound of formula (I) or (II), depending on the condition being
treated, the severity of the condition, the time of administration,
the route of administration, the rate of excretion of the compound
employed, the duration of treatment, and the age, gender, weight,
and condition of the patient, or pharmaceutical formulations may be
presented in unit dose forms containing a predetermined amount of
an active ingredient per dose. Preferred unit dosage formulations
are those containing a daily dose or sub-dose, as herein above
recited, or an appropriate fraction thereof, of an active
ingredient. Furthermore, such pharmaceutical formulations may be
prepared by any of the methods well known in the pharmacy art.
Pharmaceutical formulations may be adapted for administration by
any appropriate route, for example by the oral (including buccal or
sublingual), rectal, nasal, topical (including buccal, sublingual,
or transdermal), vaginal, or parenteral (including subcutaneous,
intramuscular, intravenous, or intradermal) route. Such
formulations may be prepared by any method known in the art of
pharmacy, for example by bringing into association the active
ingredient with the carrier(s) or excipient(s). In addition,
compounds of the present invention can be administered using
conventional drug delivery technology, for example, intra-arterial
stents.
Pharmaceutical formulations adapted for oral administration may be
presented as discrete units such as capsules or tablets; powders or
granules; solutions or suspensions in aqueous or non-aqueous
liquids; edible foams or whips; or oil-in-water liquid emulsions or
water-in-oil emulsions.
For instance, for oral administration in the form of a tablet or
capsule, the active drug component can be combined with an oral,
non-toxic pharmaceutically acceptable inert carrier such as
ethanol, glycerol, water, and the like. Powders are prepared by
comminuting the compound to a suitable fine size and mixing with a
similarly comminuted pharmaceutical carrier such as an edible
carbohydrate, as, for example, starch or mannitol. Flavoring,
preservative, dispersing, and coloring agent can also be
present.
Capsules are made by preparing a powder mixture, as described
above, and filling formed gelatin sheaths. Glidants and lubricants
such as colloidal silica, talc, magnesium stearate, calcium
stearate, or solid polyethylene glycol can be added to the powder
mixture before the filling operation. A disintegrating or
solubilizing agent such as agar-agar, calcium carbonate, or sodium
carbonate can also be added to improve the availability of the
medicament when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants,
disintegrating agents, and coloring agents can also be incorporated
into the mixture. Suitable binders include starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes, and the like.
Lubricants used in these dosage forms include sodium oleate, sodium
chloride, and the like. Disintegrators include, without limitation,
starch, methyl cellulose, agar, betonite, xanthan gum, and the
like. Tablets are formulated, for example, by preparing a powder
mixture, granulating or slugging, adding a lubricant and
disintegrant, and pressing into tablets. A powder mixture is
prepared by mixing the compound, suitable comminuted, with a
diluent or base as described above, and optionally, with a binder
such as carboxymethylcellulose, an aliginate, gelating, or
polyvinyl pyrrolidone, a solution retardant such as paraffin, a
resorption accelerator such as a quaternary salt and/or and
absorption agent such as betonite, kaolin, or dicalcium phosphate.
The powder mixture can be granulated by wetting with a binder such
as syrup, starch paste, acadia mucilage, or solutions of cellulosic
or polymeric materials and forcing through a screen. As an
alternative to granulating, the powder mixture can be run through
the tablet machine and the result is imperfectly formed slugs
broken into granules. The granules can be lubricated to prevent
sticking to the tablet forming dies by means of the addition of
stearic acid, a stearate salt, talc, or mineral oil. The lubricated
mixture is then compressed into tablets. The compounds of the
present invention can also be combined with a free flowing inert
carrier and compressed into tablets directly without going through
the granulating or slugging steps. A clear or opaque protective
coating consisting of a sealing coat of shellac, a coating of sugar
or polymeric material, and a polish coating of wax can be provided.
Dyestuffs can be added to these coatings to distinguish different
unit dosages.
Oral fluids such as solutions, syrups, and elixirs can be prepared
in dosage unit form so that a given quantity contains a
predetermined amount of the compound. Syrups can be prepared by
dissolving the compound in a suitably flavored aqueous solution,
while elixirs are prepared through the use of a non-toxic vehicle.
Solubilizers and emulsifiers such as ethoxylated isostearyl
alcohols and polyoxy ethylene sorbitol ethers, preservatives,
flavor additive such as peppermint oil or natural sweeteners, or
saccharin or other artificial sweeteners, and the like can also be
added.
Where appropriate, dosage unit formulations for oral administration
can be microencapsulated. The formulation can also be prepared to
prolong or sustain the release as for example by coating or
embedding particulate material in polymers, wax, or the like.
The compounds of formula (I) and (II), and therapeutically
acceptable salts thereof, can also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles, and multilamellar vesicles. Liposomes
can be formed from a variety of phospholipids, such as cholesterol,
stearylamine, or phophatidylcholines.
The compounds of formula (I) and (II), and therapeutically
acceptable salts thereof, may also be delivered by the use of
monoclonal antibodies as individual carriers to which the compound
molecules are coupled. The compounds may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamidephenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palitoyl residues. Furthermore, the compounds may
be coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid,
polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacrylates, and
cross-linked or amphipathic block copolymers of hydrogels.
Pharmaceutical formulations adapted for transdermal administration
may be presented as discrete patches intended to remain in intimate
contact with the epidermis of the recipient for a prolonged period
of time. For example, the active ingredient may be delivered from
the patch by iontophoresis as generally described in Pharmaceutical
Research, 3(6), 318 (1986).
Pharmaceutical formulations adapted for topical administration may
be formulated as ointments, creams, suspensions, lotions, powders,
solutions, pastes, gels, sprays, aerosols, or oils.
For treatments of the eye or other external tissues, for example
mouth and skin, the formulations are preferably applied as a
topical ointment or cream. When formulated in an ointment, the
active ingredient may be employed with either a paraffinic or a
water-miscible ointment base. Alternatively, the active ingredient
may be formulated in a cream with an oil-in-water cream base or a
water-in oil base.
Pharmaceutical formulations adapted for topical administrations to
the eye include eye drops wherein the active ingredient is
dissolved or suspended in a suitable carrier, especially an aqueous
solvent.
Pharmaceutical formulations adapted for topical administration in
the mouth include lozenges, pastilles, and mouth washes.
Pharmaceutical formulations adapted for rectal administration may
be presented as suppositories or as enemas.
Pharmaceutical formulations adapted for nasal administration
wherein the carrier is a solid include a course powder having a
particle size for example in the range 20 to 500 microns which is
administered in the manner in which snuff is taken, i.e., by rapid
inhalation through the nasal passage from a container of the powder
held close up to the nose. Suitable formulations wherein the
carrier is a liquid, for administration as a nasal spray or nasal
drops, include aqueous or oil solutions of the active
ingredient.
Pharmaceutical formulations adapted for administration by
inhalation include fine particle dusts or mists, which may be
generated by means of various types of metered, dose pressurized
aerosols, nebulizers, or insufflators.
Pharmaceutical formulations adapted for vaginal administration may
be presented as pessaries, tampons, creams, gels, pastes, foams, or
spray formulations.
Pharmaceutical formulations adapted for parenteral administration
include aqueous and non-aqueous sterile injection solutions which
may contain anti-oxidants, buffers, bacteriostats, and solutes
which render the formulation isotonic with the blood of the
intended recipient; and aqueous and non-aqueous sterile suspensions
which may include suspending agents and thickening agents. The
formulations may be presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water for
injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules, and tablets.
It should be understood that in addition to the ingredients
particularly mentioned above, the formulations may include other
agents conventional in the art having regard to the type of
formulation in question, for example those suitable for oral
administration may include flavoring agents.
A therapeutically effective amount of a compound of the present
invention will depend upon a number of factors including, for
example, the age and weight of the animal, the precise condition
requiring treatment and its severity, the nature of the
formulation, and the route of administration, and will ultimately
be at the discretion of the attendant physician or veterinarian.
However, an effective amount of a compound of formula (I) or (II)
for the treatment of neoplastic growth, for example colon or breast
carcinoma, will generally be in the range of 0.1 to 100 mg/kg body
weight of recipient (mammal) per day and more usually in the range
of 1 to 10 mg/kg body weight per day.
The compounds of the present invention and therapeutically
acceptable salts thereof, may be employed alone or in combination
with other therapeutic agents for the treatment of the
above-mentioned conditions. In particular, in anti-cancer therapy,
combination with other chemotherapeutic, hormonal, or antibody
agents is envisaged as well as combination with surgical therapy
and radiotherapy. Combination therapies according to the present
invention thus comprise the administration of at least one compound
of formula (I) or (II), or a therapeutically acceptable salt
thereof, and the use of at least one other cancer treatment method.
Preferably, combination therapies according to the present
invention comprise the administration of at least one other
pharmaceutically active agent, preferably an anti-neoplastic agent.
The compound(s) of formula (I) or (II) and the other
pharmaceutically active agent(s) may be administered together or
separately and when administered separately this may occur
simultaneously or sequentially in any order. The amounts of the
compound(s) of formula (I) or (II) and the other pharmaceutically
active agent(s) and the relative timings of administration will be
selected in order to achieve the desired combined therapeutic
effect.
The compounds of formula (I) or (II), or therapeutically acceptable
salts thereof, and at least one additional cancer treatment therapy
may be employed in combination concomitantly or sequentially in any
therapeutically appropriate combination with such other anti-cancer
therapies. In one embodiment, the other anti-cancer therapy is at
least one additional chemotherapeutic therapy including
administration of at least one anti-neoplastic agent. The
administration in combination of a compound of formula (I) or (II),
or therapeutically acceptable salts thereof, with other
anti-neoplastic agents may be in combination in accordance with the
invention by administration concomitantly in (1) a unitary
pharmaceutical composition including both compounds or (2) separate
pharmaceutical compositions each including one of the compounds.
Alternatively, the combination may be administered separately in a
sequential manner wherein one anti-neoplastic agent is administered
first and the other second or vice versa. Such sequential
administration may be close in time or remote in time.
Anti-neoplastic agents may induce anti-neoplastic effects in a
cell-cycle specific manner, i.e., are phase specific and act at a
specific phase of the cell cycle, or bind DNA and act in a non
cell-cycle specific manner, i.e., are non-cell cycle specific and
operate by other mechanisms.
Anti-neoplastic agents useful in combination with the compounds and
salts of formula (I) or (II) include the following:
(1) cell cycle specific anti-neoplastic agents including, but not
limited to, diterpenoids such as paclitaxel and its analog
docetaxel; vinca alkaloids such as vinblastine, vincristine,
vindesine, and vinorelbine; epipodophyllotoxins such as etoposide
and teniposide; fluoropyrimidines such as 5-fluorouracil and
fluorodeoxyuridine; antimetabolites such as allopurinol,
fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine,
and thioguanine; and camptothecins such as 9-amino camptothecin,
irinotecan, topotecan, CPT-11, and the various optical forms of
7-(-4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptot-
hecin;
(2) cytotoxic chemotherapeutic agents including, but not limited
to, alkylating agents such as melphalan, chlorambucil,
cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan,
carmustine, lomustine, and dacarbazine; anti-tumor antibiotics such
as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,
dacttainomycin, and mithramycin; and platinum coordination
complexes such as cisplatin, carboplatin, and oxaliplatin; and
(3) other chemotherapeutic agents including, but not limited to,
anti-estrogens such as tomixefen, toremifene, raloxifene,
droloxifene, and iodoxyfene; progesterogens such as megastrol
acetate; aromatase inhibitors such as anastrozole, letrazole,
vorazole, and exemestane; antiandrogens such as flutamide,
nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists
and antagonists such as goserelin acetate and luprolide,
testosterone 5.alpha.-dihydroreductase inhibitors such as
finasteride; metallopreteinase inhibitors such as marimastat;
antiprogestogens; urokinase plasminogen activator receptor function
inhibitors; growth factor function inhibitors such as inhibitors of
the functions of hepatocyte growth factor; erb-B2, erb-B4,
epidermal growth factor receptor (EGFR), platelet derived growth
factor receptor (PDGFR), vascular endothelial growth factor
receptor (VEGFR and TIE-2 (other than those VEGFR and TIE-2
inhibitors described in the present invention)); and other tyrosine
kinase inhibitors such as inhibitors of CDK2 and CDK4
inhibitors.
Determination of Biological Activity
The in vitro potency of compounds in inhibiting these protein
kinases may be determined by the procedures detailed below.
The potency of compounds can be determined by the amount of
inhibition of the phosphorylation of an exogenous substrate (e.g.,
synthetic peptide (Z. Songyang et al., Nature. 373:536-539) by a
test compound relative to control.
KDR Tyrosine Kinase Production Using Baculovirus System:
The coding sequence for the human KDR intra-cellular domain
(aa789-1354) was generated through PCR using cDNAs isolated from
HUVEC cells. A poly-His6 sequence was introduced at the N-terminus
of this protein as well. This fragment was cloned into transfection
vector pVL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus
(BV) was generated through co-transfection using the BaculoGold
Transfection reagent (PharMingen). Recombinant BV was plaque
purified and verified through Western analysis. For protein
production, SF-9 cells were grown in SF-900-II medium at
2.times.106/ml, and were infected at 0.5 plaque forming units per
cell (MOD. Cells were harvested at 48 hours post infection.
Purification of KDR
SF-9 cells expressing (His).sub.6 KDR(aa789-1354) were lysed by
adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137
mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 10 .mu.g/ml
aprotinin, 1 .mu.g/ml leupeptin) to the cell pellet from 1 L of
cell culture. The lysate was centrifuged at 19,000 rpm in a Sorval
SS-34 rotor for 30 mM at 4.degree. C. The cell lysate was applied
to a 5 ml NiCl.sub.2 chelating sepharose column, equilibrated with
50 mM HEPES, pH7.5, 0.3 M NaCl. KDR was eluted using the same
buffer containing 0.25 M imidazole. Column fractions were analyzed
using SDS-PAGE and an ELISA assay (below) which measures kinase
activity. The purified KDR was exchanged into 25 mM HEPES, pH7.5,
25 mM NaCl, 5 mM DTT buffer and stored at -80.degree. C.
Compounds of the present invention inhibited KDR at IC50's between
about 0.003 .mu.M and about 40 .mu.M. Preferred compounds inhibited
KDR at IC50's between about 0.003 .mu.M and about 0.1 .mu.M.
Human Tie-2 Kinase Production and Purification
The coding sequence for the human Tie-2 intra-cellular domain
(aa775-1124) was generated through PCR using cDNAs isolated from
human placenta as a template. A poly-His.sub.6 sequence was
introduced at the N-terminus and this construct was cloned into
transfection vector pVL 1939 at the Xba 1 and Not 1 site.
Recombinant BV was generated through co-transfection using the
BaculoGold Transfection reagent (PharMingen). Recombinant BV was
plaque purified and verified through Western analysis. For protein
production, SF-9 insect cells were grown in SF-900-II medium at
2.times.106/ml, and were infected at MOI of 0.5. Purification of
the His-tagged kinase used in screening was analogous to that
described for KDR.
Human Flt-1 Tyrosine Kinase Production and Purification
The baculoviral expression vector pVL1393 (Phar Mingen, Los
Angeles, Calif.) was used. A nucleotide sequence encoding poly-His6
was placed 5' to the nucleotide region encoding the entire
intracellular kinase domain of human Flt-1 (amino acids 786-1338).
The nucleotide sequence encoding the kinase domain was generated
through PCR using cDNA libraries isolated from HUVEC cells. The
histidine residues enabled affinity purification of the protein as
a manner analogous to that for KDR and ZAP70. SF-9 insect cells
were infected at a 0.5 multiplicity and harvested 48 hours post
infection.
EGFR Tyrosine Kinase Source
EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 .mu.L)
and the EGF ligand was acquired from Oncogene Research
Products/Calbiochem (Cat # PF011-100).
Expression of ZAP70
The baculoviral expression vector used was pVL 1393. (Pharmingen,
Los Angeles, Calif.) The nucleotide sequence encoding amino acids
M(H)6 LVPR.sub.9S was placed 5' to the region encoding the entirety
of ZAP70 (amino acids 1-619). The nucleotide sequence encoding the
ZAP70 coding region was generated through PCR using cDNA libraries
isolated from Jurkat immortalized T-cells. The histidine residues
enabled affinity purification of the protein (vide infra). The
LVPR.sub.9S bridge constitutes a recognition sequence for
proteolytic cleavage by thrombin, enabling removal of the affinity
tag from the enzyme. SF-9 insect cells were infected at a
multiplicity of infection of 0.5 and harvested 48 hours post
infection.
Extraction and Purification of ZAP70
SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0,
137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 .mu.g/ml
leupeptin, 10 .mu.g/ml aprotinin and 1 mM sodium orthovanadate. The
soluble lysate was applied to a chelating sepharose HiTrap column
(Pharmacia) equilibrated in 50 mM HEPES, pH 7.5, 0.3 M NaCl. Fusion
protein was eluted with 250 mM imidazole. The enzyme was stored in
buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT.
Protein Kinase Source
Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may
be commercially obtained (e.g., from Upstate Biotechnology Inc.
(Saranac Lake, N.Y.) and Santa Cruz Biotechnology Inc. (Santa Cruz,
Ca.)) or purified from known natural or recombinant sources using
conventional methods.
Enzyme Linked Immunosorbent Assay (ELISA) For PTKs
Enzyme linked immunosorbent assays (ELISA) were used to detect and
measure the presence of tyrosine kinase activity. The ELISA were
conducted according to known protocols which are described in, for
example, Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay,"
In: Manual of Clinical Immunology, 2d ed., edited by Rose and
Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C.
The disclosed protocol was adapted for determining activity with
respect to a specific PTK. For example, preferred protocols for
conducting the ELISA experiments is provided below. Adaptation of
these protocols for determining a compound's activity for other
members of the receptor PTK family, as well as non-receptor
tyrosine kinases, are well within the abilities of those in the
art. For purposes of determining inhibitor selectivity, a universal
PTK substrate (e.g., random copolymer of poly(Glu.sub.4 Tyr),
20,000-50,000 MW) was employed together with ATP (typically 5
.mu.M) at concentrations approximately twice the apparent Km in the
assay.
The following procedure was used to assay the inhibitory effect of
compounds of this invention on KDR, Flt-1, Flt-4, Tie-1, Tie-2,
EGFR, FGFR, PDGFR, IGF-1-R, c-Met, Lck, hck, Blk, Csk, Src, Lyn,
fgr, Fyn and ZAP70 tyrosine kinase activity:
Buffers and Solutions:
PGTPoly (Glu, Tyr) 4:1
Store powder at -20.degree. C. Dissolve powder in phosphate
buffered saline (PBS) for 50 mg/ml solution. Store 1 ml aliquots at
-20.degree. C. When making plates dilute to 250 .mu.g/ml in Gibco
PBS.
Reaction Buffer: 100 mM Hepes, 20 mM MgCl.sub.2, 4 mM MnCl.sub.2, 5
mM DTT, 0.02% BSA, 200 .mu.M NaVO.sub.4, pH 7.10
ATP: Store aliquots of 100 mM at -20.degree. C. Dilute to 20 .mu.M
in water
Washing Buffer: PBS with 0.1% Tween 20
Antibody Diluting Buffer: 0.1% bovine serum albumin (BSA) in
PBS
TMB Substrate: mix TMB substrate and Peroxide solutions 9:1 just
before use or use K-Blue Substrate from Neogen
Stop Solution: 1M Phosphoric Acid
Procedure
1. Plate Preparation:
Dilute PGT stock (50 mg/ml, frozen) in PBS to a 250 .mu.g/ml. Add
125 .mu.l per well of Corning modified flat bottom high affinity
ELISA plates (Corning #25805-96). Add 125 .mu.l PBS to blank wells.
Cover with sealing tape and incubate overnight 37.degree. C. Wash
1.times. with 250 .mu.l washing buffer and dry for about 2 hrs in
37.degree. C. dry incubator. Store coated plates in sealed bag at
4.degree. C. until used. 2. Tyrosine Kinase Reaction:
Prepare inhibitor solutions at a 4.times. concentration in 20% DMSO
in water.
Prepare reaction buffer
Prepare enzyme solution so that desired units are in 50 .mu.l, e.g.
for KDR make to 1 ng/.mu.l for a total of 50 ng per well in the
reactions. Store on ice.
Make 4.times.ATP solution to 20 .mu.M from 100 mM stock in water.
Store on ice
Add 50 .mu.l of the enzyme solution per well (typically 5-50 ng
enzyme/well depending on the specific activity of the kinase)
Add 25 .mu.l 4.times. inhibitor
Add 25 .mu.l 4.times. ATP for inhibitor assay
Incubate for 10 minutes at room temperature
Stop reaction by adding 50 .mu.l 0.05N HCl per well
Wash plate
**Final Concentrations for Reaction: 5 .mu.M ATP, 5% DMSO
3. Antibody Binding
Dilute 1 mg/ml aliquot of PY20-HRP (Pierce) antibody (a
phosphotyrosine antibody) to 50 ng/ml in 0.1% BSA in PBS by a 2
step dilution (100.times., then 200.times.)
Add 100 .mu.l Ab per well. Incubate 1 hr at room temp. Incubate 1
hr at 4.degree. C.
Wash 4.times. plate
4. Color Reaction
Prepare TMB substrate and add 100 .mu.l per well
Monitor OD at 650 nm until 0.6 is reached
Stop with 1M Phosphoric acid. Shake on plate reader.
Read OD immediately at 450 nm
Optimal incubation times and enzyme reaction conditions vary
slightly with enzyme preparations and are determined empirically
for each lot.
For Lck, the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4
mM MnCl.sub.2, 20 mM MgCl.sub.2, 5 mM DTT, 0.2% BSA, 200 mM
NaVO.sub.4 under the analogous assay conditions.
Compounds of formulas I-109 may have therapeutic utility in the
treatment of diseases involving both identified, including those
not mentioned herein, and as yet unidentified protein tyrosine
kinases which are inhibited by compounds of formulas 1-109.
Cdc2 Source
The human recombinant enzyme and assay buffer may be obtained
commercially (New England Biolabs, Beverly, Mass. USA) or purified
from known natural or recombinant sources using conventional
methods.
Cdc2 Assay
A protocol that can be used is that provided with the purchased
reagents with minor modifications. In brief, the reaction is
carried out in a buffer consisting of 50 mM Tris pH 7.5, 100 mM
NaCl, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl.sub.2
(commercial buffer) supplemented with fresh 300 .mu.M ATP (31
.mu.Ci/ml) and 30 .mu.g/ml histone type IIIss final concentrations.
A reaction volume of 80 .mu.L, containing units of enzyme, is run
for 20 minutes at 25 degrees C. in the presence or absence of
inhibitor. The reaction is terminated by the addition of 120 .mu.L
of 10% acetic acid. The substrate is separated from unincorporated
label by spotting the mixture on phosphocellulose paper, followed
by 3 washes of 5 minutes each with 75 mM phosphoric acid. Counts
are measured by a betacounter in the presence of liquid
scintillant.
PKC Kinase Source
The catalytic subunit of PKC may be obtained commercially
(Calbiochem).
PKC Kinase Assay
A radioactive kinase assay is employed following a published
procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M.,
Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research
Communication 3:166, 1220-1227 (1990)). Briefly, all reactions are
performed in a kinase buffer consisting of 50 mM Tris-HCl pH7.5, 10
mM MgCl.sub.2, 2 mM DTT, 1 mM EGTA, 100 .mu.M ATP, 8 .mu.M peptide,
5% DMSO and .sup.33P ATP (8Ci/mM). Compound and enzyme are mixed in
the reaction vessel and the reaction is initiated by addition of
the ATP and substrate mixture. Following termination of the
reaction by the addition of 10 .mu.L stop buffer (5 mM ATP in 75 mM
phosphoric acid), a portion of the mixture is spotted on
phosphocellulose filters. The spotted samples are washed 3 times in
75 mM phosphoric acid at room temperature for 5 to 15 minutes.
Incorporation of radiolabel is quantified by liquid scintillation
counting.
Erk2 Enzyme Source
The recombinant murine enzyme and assay buffer may be obtained
commercially (New England Biolabs, Beverly Mass. USA) or purified
from known natural or recombinant sources using conventional
methods.
Erk2 Enzyme Assay
In brief, the reaction is carried out in a buffer consisting of 50
mM Tris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM
MgCl.sub.2 (commercial buffer) supplemented with fresh 100 .mu.M
ATP (31 .mu.Ci/ml) and 30 .mu.M myelin basic protein under
conditions recommended by the supplier. Reaction volumes and method
of assaying incorporated radioactivity are as described for the PKC
assay (vide supra).
Cellular Receptor PTK Assays
The following cellular assay was used to determine the level of
activity and effect of the different compounds of the present
invention on KDR/VEGFR2. Similar receptor PTK assays employing a
specific ligand stimulus can be designed along the same lines for
other tyrosine kinases using techniques well known in the art.
VEGF-Induced KDR Phosphorylation in Human Umbilical Vein
Endothelial Cells (HUVEC) as Measured by Western Blots:
1. HUVEC cells (from pooled donors) can be purchased from Clonetics
(San Diego, Calif.) and cultured according to the manufacturer
directions. Only early passages (3-8) are used for this assay.
Cells are cultured in 100 mm dishes (Falcon for tissue culture;
Becton Dickinson; Plymouth, England) using complete EBM media
(Clonetics).
2. For evaluating a compound's inhibitory activity, cells are
trypsinized and seeded at 0.5-1.0.times.10.sup.5 cells/well in each
well of 6-well cluster plates (Costar; Cambridge, Mass.).
3. 3-4 days after seeding, plates are typically 90-100% confluent.
Medium is removed from all the wells, cells are rinsed with 5-10 ml
of PBS and incubated 18-24 h with 5 ml of EBM base media with no
supplements added (i.e., serum starvation).
4. Serial dilutions of inhibitors are added in 1 ml of EBM media
(25 .mu.M, 5 .mu.M, or 1 .mu.M final concentration to cells and
incubated for one hour at 37.degree. C. Human recombinant
VEGF.sub.165 (R & D Systems) is then added to all the wells in
2 ml of EBM medium at a final concentration of 50 ng/ml and
incubated at 37.degree. C. for 10 minutes. Control cells untreated
or treated with VEGF only are used to assess background
phosphorylation and phosphorylation induction by VEGF.
All wells are then rinsed with 5-10 ml of cold PBS containing 1 mM
Sodium Orthovanadate (Sigma) and cells are lysed and scraped in 200
.mu.l of RIPA buffer (50 mM Tris-HCl) pH7, 150 mM NaCl, 1% NP-40,
0.25% sodium deoxycholate, 1 mM EDTA) containing protease
inhibitors (PMSF 1 mM, aprotinin pepstatin leupeptin 1 .mu.g/ml, Na
vanadate 1 mM, Na fluoride 1 mM) and 1 .mu.g/ml of Dnase (all
chemicals from Sigma Chemical Company, St Louis, Mo.). The lysate
is spun at 14,000 rpm for 30 min, to eliminate nuclei.
Equal amounts of proteins are then precipitated by addition of cold
(-20.degree. C.) Ethanol (2 volumes) for a minimum of 1 hour or a
maximum of overnight. Pellets are reconstituted in Laemli sample
buffer containing 5%-mercaptoethanol (BioRad; Hercules, Calif.) and
boiled for 5 min. The proteins are resolved by polyacrylamide gel
electrophoresis (6%, 1.5 mm Novex, San Diego, Calif.) and
transferred onto a nitrocellulose membrane using the Novex system.
After blocking with bovine serum albumin (3%), the proteins are
probed overnight with anti-KDR polyclonal antibody (C20, Santa Cruz
Biotechnology; Santa Cruz, Calif.) or with anti-phosphotyrosine
monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid,
N.Y.) at 4.degree. C. After washing and incubating for 1 hour with
HRP-conjugated F(ab).sub.2 of goat anti-rabbit or goat-anti-mouse
IgG the bands are visualized using the emission chemiluminescience
(ECL) system (Amersham Life Sciences, Arlington Heights, Ill.).
In Vivo Uterine Edema Model
This assay measures the capacity of compounds to inhibit the acute
increase in uterine weight in mice which occurs in the first few
hours following estrogen stimulation. This early onset of uterine
weight increase is known to be due to edema caused by increased
permeability of uterine vasculature. Cullinan-Bove and Koss
(Endocrinology (1993), 133:829-837) demonstrated a close temporal
relationship of estrogen-stimulated uterine edema with increased
expression of VEGF mRNA in the uterus. These results have been
confirmed by the use of neutralizing monoclonal antibody to VEGF
which significantly reduced the acute increase in uterine weight
following estrogen stimulation (WO 97/42187). Hence, this system
can serve as a model for in vivo inhibition of VEGF signalling and
the associated hyperpermeability and edema.
Materials: All hormones can be purchased from Sigma (St. Louis,
Mo.) or Cal Biochem (La Jolla, Calif.) as lyophilized powders and
prepared according to supplier instructions. Vehicle components
(DMSO, Cremaphor EL) can be purchased from Sigma (St. Louis, Mo.).
Mice (Balb/c, 8-12 weeks old) can be purchased from Taconic
(Germantown, N.Y.) and housed in a pathogen-free animal facility in
accordance with institutional Animal Care and Use Committee
Guidelines. Method:
Day 1: Balb/c mice are given an intraperitoneal (i.p.) injection of
12.5 units of pregnant mare's serum gonadotropin (PMSG).
Day 3: Mice receive 15 units of human chorionic gonadotropin (hCG)
i.p.
Day 4: Mice are randomized and divided into groups of 5-10. Test
compounds are administered by i.p., i.v. or p.o. routes depending
on solubility and vehicle at doses ranging from 1-100 mg/kg.
Vehicle control group receive vehicle only and two groups are left
untreated.
Thirty minutes later, experimental, vehicle and 1 of the untreated
groups are given an i.p. injection of 17-estradiol (500 mg/kg).
After 2-3 hours, the animals are sacrificed by CO.sub.2 inhalation.
Following a midline incision, each uterus was isolated and removed
by cutting just below the cervix and at the junctions of the uterus
and oviducts. Fat and connective tissue were removed with care not
to disturb the integrity of the uterus prior to weighing (wet
weight). Uteri are blotted to remove fluid by pressing between two
sheets of filter paper with a one liter glass bottle filled with
water. Uteri are weighed following blotting (blotted weight). The
difference between wet and blotted weights is taken as the fluid
content of the uterus. Mean fluid content of treated groups is
compared to untreated or vehicle treated groups. Significance is
determined by Student's test. Non-stimulated control group is used
to monitor estradiol response.
Certain compounds of this invention which are inhibitors of
angiogenic receptor tyrosine kinases can also be shown active in a
Matrigel implant model of neovascularization. The Matrigel
neovascularization model involves the formation of new blood
vessels within a clear marble of extracellular matrix implanted
subcutaneously which is induced by the presence of proangiogenic
factor producing tumor cells (for examples see: Passaniti, A., et
al, Lab. Investig. (1992), 67(4), 519-528; Anat. Rec. (1997),
249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vasc. Biol.
(1995), 15(11), 1857-6). The model preferably runs over 3-4 days
and endpoints include macroscopic visual/image scoring of
neovascularization, microscopic microvessel density determinations,
and hemoglobin quantitation (Drabkin method) following removal of
the implant versus controls from animals untreated with inhibitors:
The model may alternatively employ bFGF or HGF as the stimulus.
The compounds of the present invention may be used in the treatment
of protein kinase-mediated conditions, such as benign and
neoplastic proliferative diseases and disorders of the immune
system. Such diseases include autoimmune diseases, such as
rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple
sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's
disease, myasthenia gravis and systemic lupus erythematosus;
psoriasis, organ transplant rejection (e.g., kidney rejection,
graft versus host disease), benign and neoplastic proliferative
diseases, human cancers such as lung, breast, stomach, bladder,
colon, pancreatic, ovarian, prostate and rectal cancer and
hematopoietic malignancies (leukemia and lymphoma), glioblastoma,
infantile hemangioma, and diseases involving inappropriate
vascularization (for example diabetic retinopathy, retinopathy of
prematurity, choroidal neovascularization due to age-related
macular degeneration, and infantile hemangiomas in human beings).
Such inhibitors may be useful in the treatment of disorders
involving VEGF mediated edema, ascites, effusions, and exudates,
including for example macular edema, cerebral edema, acute lung
injury and adult respiratory distress syndrome (ARDS). In addition,
the compounds of the invention may be useful in the treatment of
pulmonary hypertension, particularly in patients with
thromboembolic disease (J. Thorac. Cardiovasc. Surg. 2001, 122 (1),
65-73).
Synthetic Methods
Abbreviations which have been used in the descriptions of the
scheme and the examples that follow are: AIBN for
2,2'-azobis(2-methylpropionitrile); THF for tetrahydrofuran; MTBE
for methyl tert-butyl ether, PPh.sub.3 for triphenylphosphine;
o-tol.sub.3P for tri-o-tolylphosphine; dppf for
diphenylphosphinoferrocene; DMF for N,N-dimethylformamide; DME for
1,2-dimethoxyethane; NBS for N-bromosuccinimide; NMP for
N-methylpyrrolidinone; DMSO for dimethylsulfoxide; LDA for lithium
diisopropylamide; TFA for trifluoroacetic acid; min for minutes;
TBTU for O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate; and DEAD for diethyl azodicarboxylate.
The compounds and processes of the present invention will be better
understood in connection with the following synthetic schemes which
illustrate the methods by which the compounds of the invention may
be prepared. Starting materials can be obtained from commercial
sources or prepared by well-established literature methods known to
those of ordinary skill in the art. The groups A, X, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as defined
above unless otherwise noted below.
This invention is intended to encompass compounds having formula
(I) when prepared by synthetic processes or by metabolic processes.
Preparation of the compounds of the invention by metabolic
processes include those occurring in the human or animal body (in
vivo) or processes occurring in vitro.
##STR00004##
Scheme 1 shows the synthesis of compounds of formula (4). Compounds
of formula (3) can be reacted with an appropriately substituted
isocyanate (R.sup.6NCO) to provide compounds of formula (4).
Examples of solvents used in these reactions include THF,
dichloromethane, and MTBE. The reaction is typically conducted at a
temperature of about 0.degree. C. to about 25.degree. C. for about
1 hour to about 14 hours.
##STR00005##
Compounds of formula (Ia) can be prepared following the procedures
described in Scheme 2. Compounds of formula (5) can be converted to
compounds of formula (6) by treatment with hydrazine. Examples of
solvents include n-butanol, ethanol, n-pentanol, and n-hexanol. The
reaction is typically conducted at about 80.degree. C. to about
120.degree. C. for about 2 to about 12 hours. Compounds of formula
(6) where R.sup.9 is hydrogen can be converted to compounds of
formula (6) where R.sup.9 is alkenyl, alkoxyalkyl, alkyl,
heterocyclylalkyl, hydroxyalkyl, or (NR.sup.aR.sup.b)alkyl by
treatment with the appropriately substituted alkylating agent in
the presence of a base under conditions known to those of ordinary
skill in the art.
Conversion of compounds of formula (6) to compounds of formula (Ia)
can be accomplished by treatment with compounds of formula (7) in
the presence of a palladium catalyst and a base. Representative
palladium catalysts include Pd(PPh.sub.3).sub.4,
Pd(o-tol.sub.3P).sub.2Cl.sub.2, PdCl.sub.2(dppf), and
PdCl.sub.2(dppf).CH.sub.2Cl.sub.2. Examples of bases include sodium
carbonate, cesium carbonate, and potassium carbonate. Solvents
typically used in these reactions include DMF, DME, toluene,
ethanol, water, and mixtures thereof. The reaction is typically
conducted at temperatures between about 60.degree. C. and about
130.degree. C. (optionally in a microwave for about 5 to about 25
minutes) for about 4 to about 24 hours.
##STR00006##
As shown in Scheme 3, compounds of formula (8) can be converted to
compounds of formula (9) by treatment with NBS in the presence of a
radical initiator such as benzoyl peroxide AIBN. Examples of
solvents used in this reaction include CCl.sub.4, benzene, and
CHCl.sub.3. The reaction is typically conducted at about 60 to
about 80.degree. C. for about 4 to about 48 hours.
Compounds of formula (9) can be converted to compounds of formula
(5a) by treatment with a nucleophile (Z) (for example, an amine or
an alcohol). Examples of solvents used in these reactions include
THF, DMF, NMP, and DME. The reaction is typically conducted at
about 20.degree. C. to about 60.degree. C. for about 12 to about 24
hours.
Conversion of compounds of formula (5a) to compounds of formula
(6a) can be accomplished by the methods described in Scheme 2.
##STR00007##
Scheme 4 shows the synthesis of compounds of formula (Ib).
Compounds of formula (6) (prepared by the methods described in
Scheme 2) can be converted to compounds of formula (10) by
treatment with an appropriately substituted borane or other
organometallic reagent such as a stannane or organozinc reagent in
the presence of a palladium catalyst and optionally a base.
Representative palladium catalysts include Pd(PPh.sub.3).sub.4,
Pd(o-tol.sub.3P).sub.2Cl.sub.2, PdCl.sub.2(dppf), and
PdCl.sub.2(dppf).CH.sub.2Cl.sub.2. Examples of bases include sodium
carbonate, cesium carbonate, and potassium carbonate. Solvents
typically used in these reactions include DMF, DME, toluene,
ethanol, water, and mixtures thereof. The reaction is typically
conducted at temperatures between about 60.degree. C. and about
130.degree. C. for about 4 to about 24 hours.
Compounds of formula (10) can be converted to compounds of formula
(Ib) by treatment with the appropriately substituted electrophile
to generate L (i.e., an isocyanate of formula R.sup.6NCO). Examples
of solvents include dichloromethane, chloroform, THF, DMF, and
MTBE. The reaction is typically conducted at about -5.degree. C. to
about 25.degree. C. for about 12 to about 24 hours.
##STR00008##
As shown in Scheme 5, compounds of formula (II) can be reacted with
the compound of formula (12), a palladium catalyst, and potassium
acetate, then treated with compounds of formula (6) in the presence
of a palladium catalyst and a base to provide compounds of formula
(Ib). Representative palladium catalysts include
Pd(PPh.sub.3).sub.4, Pd(o-tol.sub.3P).sub.2Cl.sub.2,
PdCl.sub.2(dppf), and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2. Examples
of bases include sodium carbonate, cesium carbonate, and potassium
carbonate. Solvents typically used in these reactions include DMF,
DME, toluene, ethanol, water, and mixtures thereof. The reaction is
typically conducted at temperatures between about 60.degree. C. and
about 130.degree. C. for about 4 to about 24 hours.
##STR00009##
The synthesis of compounds of formula (Ic) is shown in Scheme 6.
Compounds of formula (13) can be reacted with the compound of
formula (12) then with compounds of formula (6) using the
conditions described in Scheme 5 to provide compounds of formula
(14). Compounds of formula (14) can be hydrolyzed to compounds of
formula (15) using conditions known to those of ordinary skill in
the art (i.e., KOH). Compounds of formula (15) can be converted to
compounds of formula (Ic) by treatment with an appropriately
substituted amine in the presence of a coupling agent under
conditions known to those of ordinary skill in the art.
##STR00010##
Compounds of formula (Id) can be prepared as described in Scheme 7.
Compounds of formula (16) can be converted to compounds of formula
(17) using the conditions described in Schemes 2 and 4. Compounds
of formula (17) can be converted to compounds of formula (18)
(where L.sup.2 is an alkenyl group and R.sup.d is
(NR.sup.aR.sup.b)carbonyl or alkoxycarbonyl) by treatment with a
palladium catalyst and a base such as triethylamine or
diisopropylethylamine. Examples of solvents include THF and
1,4-dioxane. The reaction is typically conducted at about 80 to
about 150.degree. C. for about 30 minutes to about 6 hours.
Conversion of compounds of formula (18) to compounds of formula
(19) can be accomplished by methods known to those of ordinary
skill in the art. Compounds of formula (19) can be converted to
compounds of formula (Id) by the methods described in Scheme 4.
##STR00011##
Scheme 8 shows the synthesis of compounds of formula (Ie).
Compounds of formula (21) (where Q is Br or I) can be reacted with
the compound of formula (22) in the presence of potassium
tert-butoxide to provide compounds of formula (23). Examples of
solvents used in this reaction include DMF, DME, and NMP. The
reaction is typically conducted at about 20.degree. C. to about
35.degree. C. for about 15 minutes to about 12 hours.
Compounds of formula (23) can be coupled with compounds of formula
(24) using the conditions described in Schemes 2, 4, and 7 to
provide compounds of formula (Ie).
The present invention will now be described in connection with
certain preferred embodiments which are not intended to limit its
scope. On the contrary, the present invention covers all
alternatives, modifications, and equivalents as can be included
within the scope of the claims. Thus, the following examples, which
include preferred embodiments, will illustrate the preferred
practice of the present invention, it being understood that the
examples are for the purposes of illustration of certain preferred
embodiments and are presented to provide what is believed to be the
most useful and readily understood description of its procedures
and conceptual aspects.
Compounds of the invention were named by ACD/ChemSketch version 5.0
(developed by Advanced Chemistry Development, Inc., Toronto, ON,
Canada).
Example 1
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
Example 1A
4-iodo-1H-indazol-3-amine
A mixture of 2-fluoro-6-iodobenzonitrile (2 g, 8.1 mmol) and
hydrazine hydrate (4 mL) in n-butanol (40 mL) was heated to
105-110.degree. C. for 5 hours, cooled to room temperature, poured
into water, and extracted twice with ethyl acetate. The combined
extracts were washed with water and brine, dried (MgSO.sub.4),
filtered, and concentrated to provide 1.88 g of the desired
product. R.sub.f=0.25 (5% methanol/dichloromethane).
Example 1B
N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl]urea
A 0.degree. C. mixture of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.03 g, 23
mmol) and 1-isocyanato-3-methylbenzene (2.95 mL, 23 mmol) in THF
(90 mL) was stirred at room temperature for 1 hour, concentrated,
suspended in acetonitrile, and filtered. The filter cake was dried
to provide 8.09 g of the desired product.
Example 1C
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
A mixture of Example 1A (60 mg, 0.24 mmol), Example 1B (103 mg,
0.29 mmol) and Na.sub.2CO.sub.3 (64 mg, 0.6 mmol) under a nitrogen
atmosphere was treated with DME (8 mL), water (2 mL), and
Pd(PPh.sub.3).sub.4 (14 mg, 0.012 mmol). The mixture was purged
with bubbling nitrogen for 2 minutes, heated to 80-90.degree. C.
for about 18 hours, cooled to room temperature, poured into water,
and extracted twice with ethyl acetate. The combined extracts were
washed with water and brine, dried (MgSO.sub.4), filtered, and
concentrated. The concentrate was purified by flash column
chromatography on silica gel with 5-8% methanol/dichloromethane to
provide 56 mg (66% yield) of the desired product. MS (ESI(+)) m/e
358 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.29
(s, 3H), 4.33 (s, 2H), 6.76-6.83 (m, 2H), 7.17 (t, J=7.80 Hz, 1H),
7.23-7.28 (m, 3H), 7.32 (s, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.59 (d,
J=8.48 Hz, 2H), 8.64 (s, 1H), 8.79 (s, 1H), 11.70 (s, 1H).
Example 2
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3,5-dimethoxyphenyl)urea
The desired product was prepared by substituting
1-isocyanato-3,5-dimethoxy-benzene for 1-isocyanato-3-methylbenzene
in Examples 1B-C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.73
(s, 6H), 4.33 (s, 2H), 6.15 (t, J=2.20 Hz, 1H), 6.70 (d, J=2.03 Hz,
2H), 6.78 (dd, J=5.76, 2.37 Hz, 1H), 7.22-7.31 (m, 2H), 7.39 (d,
J=8.48 Hz, 2H), 7.58 (d, J=8.81 Hz, 2H), 8.73 (s, 1H), 8.78 (s,
1H), 11.71 (s, 1H); MS (ESI(+)) m/e 404 (M+H).sup.+.
Example 3
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-chloro-3-isocyanatobenzene for
1-isocyanato-3-methylbenzene in Examples 1B-C and purifying the
crude product by preparative HPLC on a Waters Symmetry C8 column
(25 mm.times.100 mm, 7 .mu.m particle size) using a gradient of 10%
to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run
time) at a flow rate of 40 mL/min. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 6.89 (dd, J=6.44, 1.70 Hz, 1H), 7.03 (m, 1H),
7.28-7.38 (m, 4H), 7.42 (d, J=8.81 Hz, 2H), 7.61 (d, J=8.82 Hz,
2H), 7.74 (m, 1H), 9.00 (s, 1H), 9.03 (s, 1H); MS (ESI(+)) m/e 378
(M+H).sup.+; Anal. calcd. for
C.sub.20H.sub.16ClN.sub.5O.CF.sub.3CO.sub.2H: C, 52.76; H, 3.62; N,
13.98. Found: C, 52.40; H, 3.50; N, 13.86.
Example 4
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-isocyanato-3-(trifluoromethyl)benzene for
1-isocyanato-3-methylbenzene in Examples 1B-C and purifying the
product by preparative HPLC using the conditions described in
Example 3. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.86 (dd,
J=6.10, 2.03 Hz, 1H), 7.29-7.35 (m, 3H), 7.42 (d, J=8.81 Hz, 2H),
7.53 (t, J=7.97 Hz, 1H), 7.58-7.65 (m, 3H), 8.05 (s, 1H), 9.01 (s,
1H), 9.16 (s, 1H); MS (ESI(+)) m/e 412 (M+H).sup.+; Anal. calcd.
for C.sub.21H.sub.16F.sub.3N.sub.5O.0.7CF.sub.3CO.sub.2H: C, 54.77;
H, 3.43; N, 14.26. Found: C, 54.64; H, 3.32; N, 14.12.
Example 5
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
Example 5A
N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl]urea
A 0.degree. C. mixture of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.5 g, 2.28
mmol) and 1-fluoro-2-isocyanato-4-methylbenzene (0.297 mL, 2.28
mmol) in dichloromethane (15 mL) was allowed to gradually warm to
room temperature and stirred overnight. The resulting suspension
was diluted with hexanes resulting in the formation of more
precipitate, which was collected by filtration to provide 0.68 g of
the desired product. MS (ESI(+)) m/e 370.7 (M+H).sup.+.
Example 5B
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
A mixture of Example 1A (80 mg, 0.32 mmol), Example 5A (144 mg,
0.39 mmol) and Na.sub.2CO.sub.3 (58 mg) in DME (3 mL) and water (1
mL) was degassed with nitrogen for 2 minutes, treated with
Pd(PPh.sub.3).sub.4 (19 mg, 0.0161 mmol), and degassed with
nitrogen for another 2 minutes. The vial was capped and heated to
160.degree. C. for 10 minutes with stirring in a Smith Synthesizer
microwave oven (at 300 W). The reaction was concentrated and the
residue was purified by HPLC using the conditions in Example 3 to
provide 63 mg of the desired product as the trifluoroacetate salt.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 6.78-6.85
(m, 1H), 6.87 (dd, J=6.10, 1.70 Hz, 1H), 7.12 (dd, J=11.53, 8.48
Hz, 1H), 7.30-7.39 (m, 2H), 7.42 (d, J=8.81 Hz, 2H), 7.60 (d,
J=8.48 Hz, 2H), 8.01 (dd, J=7.80, 2.37 Hz, 1H), 8.54 (d, J=2.71 Hz,
1H), 9.23 (s, 1H); MS (ESI(+)) m/e 376 (M+H).sup.+; Anal calcd. for
C.sub.21H.sub.18FN.sub.5O.0.8CF.sub.3CO.sub.2H: C, 58.17; H, 4.06;
N, 15.01. Found: C, 58.17; H, 4.29; N, 15.12.
Example 6
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethyl)phen-
yl]urea
The desired product was prepared by substituting
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for
1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the
crude product as described in Example 1C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 4.33 (s, 2H), 6.79 (dd, J=5.26, 2.54 Hz, 1H),
7.24-7.31 (m, 2H), 7.42 (m, 3H), 7.52 (m, 1H), 7.61 (d, J=8.48 Hz,
2H), 8.65 (dd, J=7.29, 2.20 Hz, 1H), 8.96 (d, J=3.05 Hz, 1H), 9.32
(s, 1H), 11.72 (s, 1H); MS (ESI(+)) m/e 430 (M+H).sup.+.
Example 7
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-bromo-3-isocyanatobenzene for
1-isocyanato-3-methylbenzene in Examples 5A-B. NMR (300 MHz,
DMSO-d.sub.6) .delta. 6.87 (dd, J=6.10, 1.70 Hz, 1H), 7.13-7.18 (m,
1H), 7.25 (t, J=7.97 Hz, 1H), 7.31-7.26 (m, 3H), 7.42 (d, J=8.82
Hz, 2H), 7.61 (d, J=8.48 Hz, 2H), 7.88 (t, J=1.86 Hz, 1H), 8.99 (s,
1H); MS (ESI(-)) m/e 420, 422 (M-H).sup.-.
Example 8
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-bromo-4-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 2-bromo-4-isocyanato-1-methylbenzene for
1-isocyanato-3-methylbenzene in Examples 5A-B. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.33 (s, 3H), 6.88 (dd, J=6.10, 1.70 Hz,
1H), 7.25-7.50 (m, 7H), 7.61 (d, J=8.48 Hz, 2H), 8.85 (s, 1H), 8.93
(s, 1H); MS (ESI(-)) m/e 434, 435 (M-H).sup.-.
Example 9
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-ethyl-3-isocyanatobenzene for
1-isocyanato-3-methylbenzene in Examples 5A-B. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 1.19 (t, J=7.63 Hz, 3H), 2.58 (q, J=7.68
Hz, 2H), 6.81-6.88 (m, 2H), 7.19 (t, J=7.80 Hz, 1H), 7.25-7.36 (m,
4H), 7.40 (d, J=8.48 Hz, 2H), 7.60 (d, J=8.81 Hz, 2H), 8.70 (s,
1H), 8.85 (s, 1H); MS (ESI(+)) m/e 372 (M+H).sup.+.
Example 10
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-phenylurea
The desired product was prepared by substituting isocyanatobenzene
for 1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the
crude product as described in Example 1C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 4.33 (s, 2H), 6.78 (dd, J=5.42, 2.37 Hz, 1H),
6.98 (t, J=7.29 Hz, 1H), 7.28 (m, 4H), 7.39 (d, J=8.81 Hz, 2H),
7.48 (d, J=7.46 Hz, 2H), 7.59 (d, J=8.82 Hz, 2H), 8.72 (s, 1H),
8.81 (s, 1H), 11.70 (s, 1H); MS (ESI(+)) m/e 344 (M+H).sup.+.
Example 11
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)urea
The desired product was prepared by substituting
2-fluoro-4-isocyanato-1-methylbenzene for
1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the
crude product as described in Example 1C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.17 (s, 3H), 4.33 (s, 2H), 6.78 (dd, J=5.42,
2.71 Hz, 1H), 7.05 (dd, J=8.14, 2.03 Hz, 1H), 7.17 (t, J=8.65 Hz,
1H), 7.23-7.30 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.45 (dd, J=12.54,
2.03 Hz, 1H), 7.58 (d, J=8.81 Hz, 2H), 8.84 (s, 2H), 11.70 (s, 1H);
MS ESI(+)) m/e 376 (M+H).sup.+.
Example 12
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea
The desired product was prepared by substituting
1-fluoro-2-isocyanatobenzene for 1-isocyanato-3-methylbenzene in
Examples 5A-B and purifying the crude product as described in
Example 1C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.33 (s,
2H), 6.79 (dd, J=5.42, 2.71 Hz, 1H), 6.97-7.06 (m, 1H), 7.16 (t,
J=7.63 Hz, 1H), 7.22-7.30 (m, 3H), 7.41 (d, J=8.48 Hz, 2H), 7.60
(d, J=8.48 Hz, 2H), 8.18 (m, 1H), 8.61 (d, J=2.37 Hz, 1H), 9.22 (s,
1H), 11.71 (s, 1H); MS (ESI(+)) m/e 362 (M+H).sup.+.
Example 13
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea
The desired product was prepared by substituting
1-fluoro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzene in
Examples 5A-B and purifying the crude product as described in
Example 1C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.33 (s,
2H), 6.78 (dd, J=5.43, 2.37 Hz, 1H), 7.13 (t, J=8.99 Hz, 2H),
7.22-7.29 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.49 (m, 2H), 7.59 (d,
J=8.82 Hz, 2H), 8.80 (d, J=15.60 Hz, 2H), 11.70 (s, 1H); MS
(ESI(+)) 362 (M+H).sup.+.
Example 14
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
The desired product was prepared by substituting
1-fluoro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in
Examples 5A-B and purifying the crude product as described in
Example 1C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 4.33 (s,
2H), 6.75-6.83 (m, 2H), 7.15 (m, 1H), 7.23-7.36 (m, 3H), 7.40 (d,
J=8.48 Hz, 2H), 7.52 (m, 1H), 7.59 (d, J=8.48 Hz, 2H), 8.89 (s,
1H), 8.97 (s, 1H), 11.71 (s, 1H); MS (ESI(+)) m/e 362
(M+H).sup.+.
Example 15
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-(3-fluor-
ophenyl)urea
Example 15A
2-fluoro-6-iodo-3-methylbenzoic acid
A -78.degree. C. solution of 2-fluoro-4-iodo-1-methylbenzene (25 g,
105.9 mmol) in THF (200 mL) was treated dropwise with LDA (2M
solution in THF, 58.5 mL, 116 mmol), stirred at -78.degree. C. for
1 hour, treated with excess powdered dry ice, stirred at
-78.degree. C. for 30 minutes, and warmed to room temperature
gradually over about 18 hours. The mixture was concentrated and the
residue was partitioned between 4N NaOH and diethyl ether. The
aqueous phase was adjusted to pH 2 with 2N HCl and extracted three
times with ethyl acetate. The combined extracts were washed with
water and brine, dried (MgSO.sub.4), filtered, and concentrated to
provide 19.4 g (66% yield) of the desired product. MS (ESI(+)) m/e
279 (M+H).sup.+.
Example 15B
2-fluoro-6-iodo-3-methylbenzamide
A solution of Example 15A (19.3 g, 69.1 mmol) in thionyl chloride
(60 mL) was heated to 80.degree. C. for 3 hours, cooled to room
temperature, and concentrated. The residue was dissolved in THF
(100 mL), cooled to 0.degree. C., treated with concentrated
NH.sub.4OH (80 mL), stirred at room temperature for about 18 hours,
and concentrated. The concentrate was suspended in water and
filtered. The filter cake was washed with water and dried to
provide 18.67 g of the desired product. MS (CI/NH.sub.3) m/e 280
(M+H).sup.+.
Example 15C
2-fluoro-6-iodo-3-methylbenzonitrile
A solution of Example 15B (18.6 g, 66.7 mmol) in DMF (190 mL) was
treated dropwise with thionyl chloride (24 mL, 333 mmol), heated to
115.degree. C. for 16 hours, cooled to room temperature, poured
into ice, and extracted three times with ethyl acetate. The
combined extracts were washed with water and brine, dried
(MgSO.sub.4), filtered, and concentrated. The concentrate was
purified by flash column chromatography on silica gel with 25%
ethyl acetate/hexanes to provide 12.35 g (71% yield) of the desired
product. MS (CI/NH.sub.3) m/e 279 (M+NH.sub.4).sup.+.
Example 15D
3-(bromomethyl)-2-fluoro-6-iodobenzonitrile
A mixture of Example 15C (8.0 g, 30.6 mmol), NBS (6.54 g, 36.78
mmol), and benzoyl peroxide (0.5 g) in CCl.sub.4 (100 mL) was
heated to reflux for 36 hours during which time additional NBS (9
g) and benzoyl peroxide (1.5 g) was added in 3 portions. The
suspension was filtered and the filtrate was concentrated. The
residue was purified by flash column chromatography on silica gel
with 20% ethyl acetate/hexanes to provide 4.83 g (46% yield) of the
desired product. R.sub.f=0.27 (20% ethyl acetate/hexanes).
Example 15E
2-fluoro-6-iodo-3-(4-morpholinylmethyl)benzonitrile
A solution of Example 15D (710 mg, 2.09 mmol) and morpholine (0.546
mL, 6.25 mmol) in DMF (8 mL) was stirred at room temperature
overnight, poured into water, and extracted twice with ethyl
acetate. The combined extracts were washed with water and brine,
dried (MgSO.sub.4), filtered, and concentrated to provide 0.71 g of
the desired product. R.sub.f=0.4 (ethyl acetate).
Example 15F
4-iodo-7-(4-morpholinylmethyl)-1H-indazol-3-amine
The desired product was prepared by substituting Example 15E for
2-fluoro-6-iodobenzonitrile in Example 1A. R.sub.f=0.18 (ethyl
acetate).
Example 15G
4-(4-aminophenyl)-7-(4-morpholinylmethyl)-1H-indazol-3-amine
The desired product was prepared by substituting Example 15F and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Example
1A and 1B, respectively, in Example 1C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.42 (d, J=4.07 Hz, 4H), 3.58 (m, 4H), 3.65
(s, 2H), 4.36 (s, 2H), 5.24 (s, 2H), 6.66 (dd, J=7.80, 4.41 Hz,
3H), 7.12 (m, 3H), 11.45 (s, 1H); MS (ESI(+)) m/e 324
(M+H).sup.+.
Example 15H
N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-(3-fluoro-
phenyl)urea
A solution of Example 15G (50 mg, 0.155 mmol) in dichloromethane
was cooled to 0.degree. C., treated with
1-fluoro-3-isocyanatobenzene (0.021 mL), stirred at room
temperature overnight, and concentrated. The concentrate was
purified by preparative HPLC on a Waters Symmetry C8 column (25
mm.times.100 mm, 7 .mu.m particle size) using a gradient of 10% to
100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run
time) at a flow rate of 40 mL/min to provide 24 mg of the desired
product as the trifluoroacetate salt. .sup.1H NMR. (300 MHz,
DMSO-d.sub.6) .delta. 3.20-4.20 (m, 8H), 4.56 (s, 2H), 6.79 (m,
1H), 6.92 (d, J=7.12 Hz, 1H), 7.16 (m, 1H), 7.32 (m, 1H), 7.42 (m,
3H), 7.52 (m, 1H), 7.63 (d, J=8.81 Hz, 2H), 9.12 (s, 1H), 9.16 (s,
1H); MS (ESI(+)) m/e 461 (M+H).sup.+.
Example 16
N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-(3-methyl-
phenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-isocyanato-3-methylbenzene for
1-fluoro-3-isocyanatobenzene in Example 15H. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.29 (s, 3H), 3.20-4.20 (m, 8H), 4.56 (s,
2H), 6.80 (d, J=7.12 Hz, 1H), 6.92 (d, J=7.12 Hz, 1H), 7.17 (t,
J=7.80 Hz, 2H), 7.27 (d, J=7.23 Hz, 1H), 7.32 (s, 1H), 7.42 (m,
3H), 7.63 (d, J=8.48 Hz, 2H), 8.79 (s, 1H), 8.98 (s, 1H).
Example 17
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-[2-fluor-
o-5-(trifluoromethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for
1-fluoro-3-isocyanatobenzene in Example 15H. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 3.20-4.10 (m, 8H), 4.56 (s, 2H), 6.92 (d,
J=7.12 Hz, 1H), 7.38-7.47 (m, 4H), 7.52 (m, 1H), 7.64 (d, J=8.81
Hz, 2H), 8.64 (dd, J=7.46, 2.03 Hz, 1H), 9.00 (d, J=2.71 Hz, 1H),
9.40 (s, 1H); MS (ESI(+)) m/e 529 (M+H).sup.+.
Example 18
N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl)}-N'-[4-fluor-
o-3-(trifluoromethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for
1-fluoro-3-isocyanatobenzene in Example 15H. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 3.15-4.05 (m, 8H), 4.56 (s, 2H), 6.92 (d,
J=7.12 Hz, 1H), 7.44 (m, 4H), 7.64 (d, J=8.81 Hz, 2H), 7.66 (m,
1H), 8.05 (dd, J=6.44, 2.71 Hz, 1H), 9.18 (s, 1H), 9.30 (s, 1H); MS
(ESI(+)) m/e 529 (M+H).sup.+.
Example 19
N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N'-[3-(trifl-
uoromethyl)phenyl]urea
A solution of Example 15F (80 mg, 0.22 mmol) and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluor-
omethyl)phenyl]urea (108 mg, 0.268 mmol) in toluene (2 mL) and
ethanol (1.5 mL) was treated with a solution of Na.sub.2CO.sub.3
(58 mg) in water (1 mL), degassed with nitrogen for 2 minutes,
treated with Pd(PPh.sub.3).sub.4 (13 mg, 0.011 mmol), and degassed
with nitrogen for another 2 minutes. The vial was capped and heated
to 140-150.degree. C. for 8-10 minutes with stirring in a Smith
Synthesizer microwave oven (at 300 W). The reaction was poured into
water and extracted three times with ethyl acetate. The combined
extracts were washed with water and brine, dried (MgSO.sub.4),
filtered, and concentrated. The concentrate was purified by HPLC
using the conditions in Example 15H to provide 55 mg of the desired
product as the trifluoroacetate salt. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 3.10-4.08 (m, 8H), 4.55 (s, 2H), 6.92 (d,
J=7.12 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.38-7.47 (m, 3H), 7.53
(t, J=7.80 Hz, 1H), 7.58-7.69 (m, 3H), 8.06 (s, 1H), 9.17 (s, 1H),
9.30 (s, 1H); MS (ESI(+)) m/e 511 (M+H).sup.+.
Example 20
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N-
'-(3-chlorophenyl)urea
Example 20A
4-iodo-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-3-amine
The desired product was prepared by substituting 1-methylpiperazine
for morpholine in Examples 15E-F. MS (ESI(+)) m/e 372
(M+H).sup.+.
Example 20B
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N-
'-(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 20A and
N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]urea for Example 15F and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluor-
omethyl)phenyl]urea, respectively, in Example 19. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.97
(s, 2H), 6.85 (d, J=7.12 Hz, 1H), 7.03 (m, 1H), 7.25-7.33 (m, 3H),
7.40 (d, J=8.48 Hz, 2H), 7.62 (d, J=8.48 Hz, 2H), 7.74 (m, 1H),
9.14 (s, 1H), 9.17 (s, 1H); MS (ESI(+)) m/e 490 (M+H).sup.+.
Example 21
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N-
'-(3-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 20A and
N-(3-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]urea for Example 15F and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluor-
omethyl)phenyl]urea, respectively, in Example 19. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 2.79 (s, 3H), 3.00-3.50
(m, 8H), 3.95 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 6.84 (d, J=7.46 Hz,
1H), 7.17 (t, J=7.63 Hz, 1H), 7.23-7.29 (m, 2H), 7.32 (s, 1H), 7.39
(d, J=8.48 Hz, 2H), 7.61 (d, J=8.81 Hz, 2H), 8.76 (s, 1H), 8.94 (s,
1H); MS (ESI(+)) m/e 470 (M+H).sup.+.
Example 22
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N-
'-(3-fluorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 20A and
N-(3-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]urea for Example 15F and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluor-
omethyl)phenyl]urea, respectively, in Example 19. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.95
(s, 2H), 6.75-6.86 (m, 2H), 7.15 (m, 1H), 7.25-7.35 (m, 2H), 7.40
(d, J=8.81 Hz, 2H), 7.52 (m, 1H), 7.62 (d, J=8.48 Hz, 2H), 9.09 (s,
1H), 9.15 (s, 1H); MS (ESI(+)) m/e 474 (M+H).sup.+.
Example 23
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N-
-[3-(trifluoromethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 20A for Example 15F in Example 19. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.80 (s, 3H), 3.00-3.50 (m, 8H),
3.97 (s, 2H), 6.85 (d, J=7.46 Hz, 1H), 7.28 (d, J=7.12 Hz, 1H),
7.32 (d, J=7.80 Hz, 1H), 7.41 (d, J=8.81 Hz, 2H), 7.58-7.66 (m,
3H), 8.06 (s, 1H), 8.06 (s, 1H), 9.18 (s, 1H), 9.32 (s, 1H); MS
(ESI(+)) m/e 524 (M+H).sup.+.
Example 24
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N-
'-[2-fluoro-5-(trifluoromethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 20A and
N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-[4-(4,4,5,5-tetramethyl-1,3,2-d-
ioxaborolan-2-yl)phenyl]urea for Example 15F and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluor-
omethyl)phenyl]urea, respectively, in Example 19. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.95
(d, J=2.37 Hz, 2H), 6.84 (d, J=7.12 Hz, 1H), 7.28 (d, J=7.12 Hz,
1H), 7.38-7.45 (m, 3H), 7.52 (m, 1H), 7.62 (d, J=8.48 Hz, 2H), 8.64
(dd, J=7.29, 2.20 Hz, 1H), 8.99 (d, J=2.71 Hz, 1H), 9.38 (s, 1H);
MS (ESI(+)) m/e 542 (M+H).sup.+.
Example 25
N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N-
'-(2-fluoro-5-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 20A and
N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)phenyl]urea for Example 15F and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'[3-(trifluoro-
methyl)phenyl]urea, respectively, in Example 19. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 2.79 (s, 3H), 3.00-3.50
(m, 8H), 3.96 (s, 2H), 6.78-6.86 (m, 2H), 7.12 (dd, J=11.36, 8.31
Hz, 1H), 7.27 (d, J=7.46 Hz, 1H), 7.40 (d, J=8.81 Hz, 2H), 7.60 (d,
J=8.48 Hz, 2H), 7.99 (dd, J=7.97, 1.86 Hz, 1H), 8.56 (d, J=2.71 Hz,
1H), 9.25 (s, 1H); MS (ESI(+)) m/e 488 (M+H).sup.+.
Example 26
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
Example 26A
2,3-difluoro-6-iodobenzonitrile
The desired product was prepared by substituting
1,2-difluoro-4-iodobenzene for 2-fluoro-4-iodo-1-methylbenzene in
Examples 15A-C.
Example 26B
4-(4-aminophenyl)-7-fluoro-1H-indazol-3-amine
The desired product was prepared by substituting Example 26A for
Example 15E in Examples 15F-G. MS (ESI(+)) m/e 243 (M+H).sup.+.
Example 26C
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 26B and 1-bromo-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.73 (dd,
J=7.80, 4.07 Hz, 1H), 7.13 (dd, J=11.19, 7.80 Hz, 1H), 7.16 (m,
1H), 7.25 (t, J=7.97 Hz, 1H), 7.34 (m, 1H), 7.38 (d, J=8.48 Hz,
2H), 7.59 (d, J=8.48 Hz, 2H), 7.88 (t, J=2.03 Hz, 1H), 8.91 (s,
1H), 8.94 (s, 1H); MS (ESI(+)) m/e 440, 442 (M+H).sup.+.
Example 27
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 26B and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.74 (dd,
J=7.80, 4.07 Hz, 1H), 7.03 (td, J=4.41, 2.37 Hz, 1H), 7.13 (dd,
J=11.19, 7.80 Hz, 1H), 7.27-7.35 (m, 2H), 7.38 (d, J=8.48 Hz, 2H),
7.59 (d, J=8.48 Hz, 2H), 7.74 (m, 1H), 8.92 (s, 1H), 8.96 (s, 1H);
MS (ESI(+)) m/e 396 (M+H).sup.+.
Example 28
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phen-
yl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 26B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 6.75 (dd, J=7.80, 4.07 Hz, 1H),
7.14 (dd, J=11.19, 7.80 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d,
J=8.48 Hz, 2H), 7.53 (t, J=7.80 Hz, 1H), 7.61 (m, 3H), 8.04 (s,
1H), 8.98 (s, 1H), 9.14 (s, 1H); MS (ESI(-)) m/e 615
(M-H).sup.-.
Example 29
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 26B and 1-isocyanato-3-methylbenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.29 (s,
3H), 6.75 (dd, J=7.80, 4.41 Hz, 1H), 6.80 (d, J=7.46 Hz, 1H), 7.15
(m, 2H), 7.25 (m, 1H), 7.32 (s, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.59
(d, J=8.48 Hz, 2H), 8.66 (s, 1H), 8.82 (s, 1H); MS (ESI(+)) m/e 376
(M+H).sup.+.
Example 30
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 26B and 3-isocyanatobenzonitrile for Example
15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.73 (dd, J=7.80, 4.41
Hz, 1H), 7.12 (dd, J=11.19, 7.80 Hz, 1H), 7.39 (d, J=8.81 Hz, 2H),
7.43 (dt, J=7.71, 1.40 Hz, 1H), 7.51 (t, J=7.97 Hz, 1H), 7.60 (d,
J=8.48 Hz, 2H), 7.70 (ddd, J=8.22, 2.29, 1.36 Hz, 1H), 8.00 (t,
J=1.70 Hz, 1H), 9.00 (s, 1H), 9.09 (s, 1H); MS (ESI(+)) m/e 387
(M+H).sup.+.
Example 31
N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluo-
ro-5-methylphenyl)urea
Example 31A
7-[(dimethylamino)methyl]-4-iodo-1H-indazol-3-amine
The desired product was prepared by substituting N,N-dimethylamine
for morpholine in Examples 15E-F. MS (ESI(+)) m/e 317
(M+H).sup.+.
Example 31B
N-(4-{3-amino-7-[dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fluor-
o-5-methylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 31A and
N-(2-fluoro-5-methylphenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)phenyl]urea for Example 15F and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluor-
omethyl)phenyl]urea, respectively, in Example 19. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 2.82 (s, 6H), 4.51 (s,
2H), 6.82 (m, 1H), 6.91 (d, J=7.12 Hz, 1H), 7.12 (dd, J=11.53, 8.48
Hz, 1H), 7.43 (d, J=8.81 Hz, 2H), 7.43 (d, J=6.78 Hz, 1H), 7.62 (d,
J=6.44 Hz, 2H), 7.99 (dd, J=7.80, 2.03 Hz, 1H), 8.56 (d, J=2.71 Hz,
1H), 9.26 (s, 1H); MS (ESI(+)) m/e 433 (M+H).sup.+; Anal. calcd.
for C.sub.24H.sub.25FN.sub.6O.2.3CF.sub.3CO.sub.2H: C, 49.44; H,
3.96; H, 12.10. Found: C, 49.51; H, 3.78; N, 12.31.
Example 32
N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-chlo-
rophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 31A and
N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]urea for Example 15F and
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluor-
omethyl)phenyl]urea, respectively, in Example 19. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.82 (s, 6H), 4.50 (s, 2H), 6.91 (d,
J=7.12 Hz, 1H), 7.03 (m, 1H), 7.28-7.36 (m, 2H), 7.40-7.45 (m, 3H),
7.63 (d, J=8.82 Hz, 2H), 7.74 (m, 1H), 9.07 (s, 1H), 9.09 (s, 1H);
MS (ESI(+)) m/e 435 (M+H).sup.+; Anal calcd. for
C.sub.23H.sub.23ClN.sub.6O.2.2CF.sub.3CO.sub.2H: C, 47.99; H, 3.70;
N, 12.25. Found: C, 48.01; H, 3.41; N, 12.52.
Example 33
N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(tri-
fluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 31A for Example 15F in Example 19. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 2.82 (s, 6H), 4.50 (s, 2H),
6.91 (d, J=7.46 Hz, 1H), 7.33 (d, J=7.46 Hz, 1H), 7.43 (d, J=8.48
Hz, 2H), 7.43 (d, J=7.46 Hz, 1H), 7.53 (t, J=7.80 Hz, 1H), 7.61 (d,
J=8.82 Hz, 1H), 7.65 (d, J=8.48 Hz, 2H), 8.06 (s, 1H), 9.13 (s,
1H), 9.26 (s, 1H); MS (ESI(+)) m/e 469 (M+H).sup.+.
Example 34
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
Example 34A
4-iodo-1-methyl-1H-indazol-3-amine
The desired product was prepared by substituting N-methylhydrazine
for hydrazine hydrate in Example 1A. MS (ESI(+)) m/e 274
(M+H).sup.+.
Example 34B
4-(4-aminophenyl)-1-methyl-1H-indazol-3-amine
The desired product was prepared by substituting Example 34A and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Example
1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 239
(M+H).sup.+.
Example 34C
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting
1-isocyanato-3-methylbenzene and Example 34B for
1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in
Example 15H. The resulting product was puffed by flash column
chromatography on silica gel with 5-8% methanol/dichloromethane to
provide the desired product. MS (ESI(+)) m/e 372 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 3.79 (s,
3H), 4.39 (s, 2H), 6.79 (dd, J=6.10, 1.70 Hz, 2H), 7.17 (t, J=7.80
Hz, 1H), 7.24-7.40 (m, 6H), 7.59 (d, J=8.48 Hz, 2H), 8.64 (s, 1H),
8.80 (s, 1H).
Example 35
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-phenylurea
The desired product was prepared as the trifluoroacetate salt by
substituting isocyanatobenzene and Example 34B for
1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in
Example 15H. MS (ESI(+)) m/e 372 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.79 (s, 3H), 6.80 (dd, J=6.55, 0.94 Hz, 1H),
6.98 (t, J=7.49 Hz, 1H), 7.39 (d, J=8.42 Hz, 2H), 7.28-7.36 (m,
4H), 7.47 (d, J=7.49 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 8.70 (s,
1H), 8.80 (s, 1H).
Example 36
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(2-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-isocyanato-2-methylbenzene and Example 34B for
1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in
Example 15H. MS (ESI(+)) m/e 372 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 2.27 (s, 3H), 3.79 (s, 3H), 4.38 (s, 2H),
6.80 (d, J=6.55 Hz, 1H), 6.96 (t, J=7.96 Hz, 1H), 7.16 (t, J=7.18
Hz, 1H), 7.19 (d, J=7.49 Hz, 1H), 7.30-7.36 (m, 2H), 7.39 (d,
J=8.42 Hz, 2H), 7.60 (d, J=6.55 Hz, 2H), 7.84 (d, J=7.18 Hz, 1H),
7.97 (s, 1H), 9.15 (s, 1H).
Example 37
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(4-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-isocyanato-4-methylbenzene and Example 34B for
1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in
Example 15H. MS (ESI(+)) m/e 372 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 2.25 (s, 3H), 3.79 (s, 3H), 6.80 (dd, J=6.55,
1.25 Hz, 1H), 7.10 (d, J=8.11 Hz, 2H), 7.30-7.39 (m, 6H), 7.58 (d,
J=8.42 Hz, 2H), 8.59 (s, 1H), 8.76 (s, 1H).
Example 38
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-isocyanato-3-methoxybenzene and Example 34B for
1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in
Example 15H. MS (ESI(+)) m/e 388 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.74 (s, 3H), 3.80 (s, 3H), 6.57 (dd, J=8.11,
2.50 Hz, 1H), 6.82 (dd, J=6.71, 1.09 Hz, 1H), 6.96 (dd, J=7.96,
1.09 Hz, 1H), 7.19 (t, J=8.11 Hz, 1H), 7.21 (t, J=2.18 Hz, 1H),
7.32-7.40 (m, 4H), 7.59 (d, J=8.42 Hz, 2H), 8.73 (s, 1H), 8.81 (s,
1H).
Example 39
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 34B for Example 15G in Example 15H. MS
(ESI(+)) m/e 376 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.79 (s, 3H), 4.37 (s, 2H), 6.77-6.81 (m, 1H), 6.80 (dd,
J=6.55, 1.25 Hz, 1H), 7.14 (dd, J=8.11, 1.25 Hz, 1H), 7.29-7.36 (m,
3H), 7.40 (d, J=8.42 Hz, 2H), 7.51 (dt, J=11.85, 2.18 Hz, 1H), 7.59
(d, J=8.42 Hz, 2H), 8.87 (s, 1H), 8.94 (s, 1H).
Example 40
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-chloro-3-isocyanatobenzene and Example 34B for
1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in
Example 15H. MS (ESI(+)) m/e 376 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.79 (s, 3H), 4.22-4.56 (br s, 2H), 6.80 (dd,
J=6.55, 1.25 Hz, 1H), 7.03 (dt, J=6.63, 2.14 Hz, 1H), 7.28-7.36 (m,
4H), 7.40 (d, J=8.42 Hz, 2H), 7.60 (d, J=8.42 Hz, 2H), 7.73 (s,
1H), 8.89 (s, 1H), 8.93 (s, 1H).
Example 41
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-bromo-3-isocyanatobenzene and Example 34B for
1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in
Example 15H. MS (ESI(+)) m/e 384, 386 (M+H).sup.+; NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.79 (s, 3H), 4.40 (s, 2H), 6.80 (dd, J=6.71,
1.09 Hz, 1H), 7.16 (d, J=8.11 Hz, 1H), 7.25 (t, J=7.96 Hz, 1H),
7.30-7.36 (m, 3H), 7.39 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.42 Hz,
2H), 7.88 (t, J=1.87 Hz, 1H), 8.89 (s, 1H), 8.91 (s, 1H).
Example 42
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phen-
yl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-isocyanato-3-(trifluoromethyl)benzene and Example
34B for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively,
in Example 15H. MS (ESI(+)) m/e 426 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 3.80 (s, 3H), 6.81 (dd, J=6.71, 1.09 Hz,
1H), 7.31-7.37 (m, 3H), 7.40 (d, J=8.42 Hz, 2H), 7.53 (t, J=7.80
Hz, 1H), 7.60 (d, J=9.05 Hz, 1H), 7.61 (d, J=8.73 Hz, 2H), 8.03 (s,
1H), 8.94 (s, 1H), 9.10 (s, 1H).
Example 43
N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-fluoro-2-isocyanato-4-methylbenzene and Example 34B
for 1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in
Example 15H. MS (ESI(+)) m/e 390 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 2.28 (s, 3H), 3.80 (s, 3H), 6.81 (d, J=5.93
Hz, 2H), 7.11 (dd, J=11.39, 8.27 Hz, 1H), 7.31-7.37 (m, 2H), 7.40
(d, J=8.73 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 8.00 (dd, J=7.64, 1.72
Hz, 1H), 8.52 (d, J=2.50 Hz, 1H), 9.20 (s, 1H).
Example 44
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-methylphenyl)urea
Example 44A
N-(4-bromo-2-fluorophenyl)-N'-(3-methylphenyl)urea
A 0.degree. C. solution of 4-bromo-2-fluoroaniline (1 g, 5.26 mmol)
in dichloromethane (10 mL) was treated dropwise with
1-isocyanato-3-methylbenzene (0.71 mL, 5.26 mmol), warmed to room
temperature, stirred for 18 hours, and filtered. The filter cake
was washed with dichloromethane and dried to provide 0.62 g of the
desired product. MS (ESI(-)) m/e 321 (M-H).sup.-.
Example 44B
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-methylphenyl)urea
A mixture of Example 44A (100 mg, 0.31 mmol),
bis(pinacolato)diboron (86 mg, 0.33 mmol), Pd(dppf)Cl.sub.2 (10 mg)
and potassium acetate (270 mg) in DMF (3 mL) was heated to
80.degree. C. for 2 hours, treated with Example 1A (64 mg, 0.24
mmol), Pd(dppf)Cl.sub.2 (6 mg), Na.sub.2CO.sub.3 (78 mg), and water
(1 mL), heated to 80.degree. C. for 18 hours, cooled to room
temperature, and concentrated. The concentrate was purified by
preparative HPLC using the conditions described in Example 15H to
provide 27 mg of the desired product as the trifluoroacetate salt.
MS (ESI(+)) m/e 376 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.28 (d, J=7.12 Hz, 3H), 6.82 (d, J=6.78 Hz,
1H), 6.86 (t, J=3.90 Hz, 1H), 7.18 (t, J=7.63 Hz, 1H), 7.26 (d,
J=8.48 Hz, 2H), 7.31-7.34 (m, 3H), 7.37 (dd, J=12.21, 1.70 Hz, 1H),
8.30 (t, J=8.65 Hz, 1H), 8.66 (d, J=2.37 Hz, 1H), 9.05 (s, 1H).
Example 45
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-fluorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-fluoro-3-isocyanatobenzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 380
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 6.82 (td,
J=8.42, 1.87 Hz, 1H), 6.86 (t, J=3.90 Hz, 1H), 7.12 (dd, J=8.11,
1.25 Hz, 1H), 7.28 (dd, J=8.27, 1.72 Hz, 1H), 7.32 (m, 3H), 7.38
(dd, J=12.01, 2.03 Hz, 1H), 7.53 (dt, J=11.85, 2.18 Hz, 1H), 8.26
(t, J=8.42 Hz, 1H), 8.72 (d, J=2.18 Hz, 1H), 9.33 (s, 1H).
Example 46
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3,5-dimethylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-isocyanato-3,5-dimethylbenzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 390
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 2.25 (s,
6H), 6.65 (s, 1H), 6.85 (t, J=3.90 Hz, 1H), 7.10 (br s, 2H), 7.26
(d, J=8.42 Hz, 1H), 7.30 (d, J=4.06 Hz, 2H), 7.36 (dd, J=12.32,
1.72 Hz, 1H), 8.29 (t, J=8.42 Hz, 1H), 8.63 (d, J=2.50 Hz, 1H),
8.96 (s, 1H).
Example 47
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-ethylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-isocyanato-3-ethylbenzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 390
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 1.19 (t,
J=7.49 Hz, 3H), 2.59 (q, J=7.80 Hz, 2H), 6.85-6.87 (m, 2H), 7.21
(t, J=7.80 Hz, 1H), 7.28 (m, J=4.06 Hz, 2H), 7.31 (br s, 1H), 7.32
(br s, 1H), 7.34 (br s, 1H), 7.37 (dd, J=12.17, 1.87 Hz, 1H), 8.30
(t, J=8.42 Hz, 1H), 8.64 (d, J=2.18 Hz, 1H), 9.06 (s, 1H).
Example 48
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chloro-4-fluorophenyl-
)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 2-chloro-1-fluoro-4-isocyanatobenzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 414
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 6.83 (dd,
J=4.68, 3.12 Hz, 1H), 7.24-7.40 (m, 6H), 7.84 (dd, J=6.55, 2.50 Hz,
1H), 8.23 (t, J=8.58 Hz, 1H), 8.71 (s, 1H), 9.28 (s, 1H).
Example 49
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-fluoro-4-methylphenyl-
)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 2-fluoro-4-isocyanato-1-methylbenzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 394
(M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 2.18 (s,
3H), 6.85 (m, 1H), 7.03 (dd, J=8.11, 1.87 Hz, 1H), 7.19 (t, J=8.58
Hz, 1H), 7.27 (dd, J=8.27, 1.72 Hz, 1H), 7.30 (br s, 1H), 7.31 (s,
1H), 7.37 (dd, J=12.17, 2.18 Hz, 1H), 7.46 (dd, J=12.48, 2.18 Hz,
1H), 8.26 (t, J=8.58 Hz, 1H), 8.67 (d, J=2.18 Hz, 1H), 9.20 (s,
1H).
Example 50
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 1-chloro-3-isocyanatobenzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(-)) m/e 394
(M-H).sup.-; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 6.85 (t,
J=3.84 Hz, 1H), 7.05 (d, J=7.80, 1H), 7.26-7.35 (m, 5H), 7.38 (dd,
J=12.17, 1.87 Hz, 1H), 7.75 (t, J=2.03 Hz, 1H), 8.25 (t, J=8.42 Hz,
1H), 8.72 (d, J=2.18 Hz, 1H), 9.30 (s, 1H).
Example 51
N-[4-(3-amino-7-bromo-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting
3-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile
in Examples 1A-C. MS (ESI(-)) m/e 434, 436 (M-H).sup.-; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 4.46 (s, 2H), 6.73
(d, J=7.46 Hz, 1H), 6.80 (d, J=6.78 Hz, 1H), 7.17 (t, J=7.63 Hz,
1H), 7.24-7.32 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.50 (d, J=7.80
Hz, 1H), 7.60 (d, J=8.14 Hz, 2H), 8.64 (s, 1H), 8.82 (s, 1H), 12.08
(s, 1H).
Example 52
N-{-4-[3-amino-1-(2-hydroxyethyl)-1H-indazol-4-yl]phenyl}-N'-(3-methylphen-
yl)urea
The desired product was prepared by substituting 2-hydrazinoethanol
for hydrazine hydrate in Examples 1A-C. MS (ESI(+)) m/e 402
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.29 (s,
3H), 3.74 (t, J=5.76 Hz, 2H), 4.20 (t, J=5.59 Hz, 2H), 6.79 (d,
J=6.78 Hz, 1H), 6.80 (d, J=7.12 Hz, 1H), 7.17 (t, J=7.63 Hz, 1H),
7.23-7.40 (m, 6H), 7.59 (d, J=8.81 Hz, 2H), 8.65 (s, 1H), 8.80 (s,
1H).
Example 53
2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-phenylacetamide
Example 53A
methyl[4-(3-amino-1H-indazol-4-yl)phenyl]acetate
The desired product was prepared by substituting methyl
(4-bromophenyl)acetate and K.sub.3PO.sub.4 for Example 44A and
Na.sub.2CO.sub.3, respectively, in Example 44B. Additionally the
reaction was carried our under anhydrous conditions. MS (ESI(+))
m/e 304 (M+H).sup.+.
Example 53B
[4-(3-amino-1H-indazol-4-yl)phenyl]acetic acid
A solution of Example 53A (140 mg) in 1:1 methanol/10% NaOH (1 mL)
was stirred at room temperature for 2 hours and adjusted to pH 3
with 10% HCl. The resulting precipitate was collected by filtration
to provide 108 mg of the desired product. MS (ESI(+)) m/e 268
(M+H).sup.+.
Example 53C
2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-phenylacetamide
A mixture of Example 53B (40 mg, 015 mmol), diisopropylethylamine
(0.078 mL, 0.45 mmol), TBTU (57 mg, 0.18 mmol), and aniline in THF
(1 mL) was stirred for 18 hours at room temperature and
concentrated. The residue was purified by preparative HPLC using
the conditions described in Example 15H to provide 15 mg of the
desired product as the trifluoroacetate salt. MS (ESI(+)) m/e 343
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.74 (s,
2H), 6.84 (dd, J=5.09, 3.05 Hz, 1H), 7.02-7.07 (m, 1H), 7.28-7.33
(m, 4H), 7.43-7.50 (m, 4H), 7.62 (d, J=7.80 Hz, 2H).
Example 54
2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(3-chlorophenyl)acetamide
The desired product was prepared as the trifluoroacetate salt by
substituting 3-chloroaniline for aniline in Example 53C. MS
(ESI(+)) m/e 377 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.75 (s, 1H), 6.84 (dd, J=5.30, 2.50 Hz, 1H), 7.11 (dd,
J=7.96, 2.03 Hz, 1H), 7.31-7.36 (m, 3H), 7.44-7.49 (m, 6H), 7.85
(d, J=1.87 Hz, 1H), 10.39 (s, 1H).
Example 55
2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide
The desired product was prepared as the trifluoroacetate salt by
substituting 4-fluoro-3-methylaniline for aniline in Example 53C.
MS (ESI(+)) m/e 375 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 2.20 (d, J=1.56 Hz, 3H), 3.71 (s, 2H), 6.84
(dd, J=5.46, 2.34 Hz, 1H), 7.07 (t, J=9.20 Hz, 1H), 7.31 (s, 1H),
7.32 (d, J=3.43 Hz, 1H), 7.40-7.60 (m, 3H), 7.45 (d, J=4.99 Hz,
2H), 7.54 (dd, J=7.02, 2.34 Hz, 1H), 10.16 (s, 1H).
Example 56
2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-[3-(trifluoromethyl)phenyl]acetami-
de
The desired product was prepared by substituting
3-(trifluoromethyl)aniline for aniline in Example 53C, then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 411
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.77 (s,
2H), 4.29 (s, 2H), 6.79 (dd, J=4.41, 3.39 Hz, 1H), 7.27 (s, 1H),
7.28 (d, J=1.36 Hz, 1H), 7.40-7.49 (m, 3H), 7.46 (d, J=3.39 Hz,
2H), 7.56 (t, J=7.63 Hz, 1H), 7.81 (d, J=9.83 Hz, 1H), 8.14 (s,
1H), 10.57 (s, 1H), 11.74 (s, 1H).
Example 57
2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide
The desired product was prepared as the trifluoroacetate salt by
substituting 3-methylaniline for aniline in Example 53C. MS
(ESI(+)) m/e 357 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.27 (s, 3H), 3.72 (s, 2H), 6.83 (dd, J=4.75, 3.05 Hz, 1H),
6.86 (d, J=7.46 Hz, 1H), 7.18 (t, J=7.80 Hz, 1H), 7.30 (s, 1H),
7.32 (d, J=2.03 Hz, 1H), 7.39-7.49 (m, 6H), 10.13 (s, 1H).
Example 58
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
Example 58A
2-fluoro-6-iodo-3-methoxybenzonitrile
The desired product was prepared by substituting
2-fluoro-4-iodo-1-methoxybenzene for
2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.
Example 58B
4-(4-aminophenyl)-7-methoxy-1H-indazol-3-amine
The desired product was prepared by substituting Example 58A for
Example 15E in Examples 15F-G. MS (ESI(+)) m/e 290 (M+H).sup.+.
Example 58C
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 58B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 388
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.29 (s,
3H), 3.92 (s, 3H), 4.30 (s, 2H), 6.69 (d, J=7.80 Hz, 1H), 6.78 (d,
J=7.79 Hz, 1H), 6.80 (d, J=7.46 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H),
7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J=8.48 Hz, 2H), 7.55 (d,
J=8.82 Hz, 2H), 8.62 (s, 1H), 8.75 (s, 1H), 11.86 (s, 1H).
Example 59
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluorom-
ethyl)phenyl]urea
The desired product was prepared by substituting Example 58B and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. MS (ESI(-)) m/e 458
(M-H).sup.-; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 3.93 (s,
3H), 4.30 (s, 2H), 6.71 (d, J=7.80 Hz, 1H), 6.79 (d, J=7.80 Hz,
1H), 7.38 (d, J=8.48 Hz, 2H), 7.41 (m; 1H), 7.50 (d, J=10.85 Hz,
1H), 7.58 (d, J=8.82 Hz, 2H), 8.65 (dd, J=7.46, 2.03 Hz, 1H), 8.95
(d, J=2.71 Hz, 1H), 9.29 (s, 1H), 11.88 (s, 1H).
Example 60
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-phenylurea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 58B and isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 374 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.94 (s, 3H), 6.75 (d, J=7.49 Hz, 1H), 6.84 (d, J=7.80 Hz,
1H), 6.98 (t, J=7.33 Hz, 1H), 7.29 (t, J=7.95 Hz, 2H), 7.36 (d,
J=8.74 Hz, 2H), 7.47 (d, J=7.49 Hz, 2H), 7.57 (d, J=8.42 Hz, 2H),
8.71 (s, 1H), 8.79 (s, 1H).
Example 61
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 58B and 1-bromo-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 452 and 454 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 3.94 (s, 3H), 6.73 (d, J=7.80 Hz,
1H), 6.82 (d, J=7.80 Hz, 1H), 7.16 (d, J=8.73 Hz, 1H), 7.25 (t,
J=8.11 Hz, 1H), 7.33 (d, J=9.36 Hz, 1H), 7.36 (d, J=8.73 Hz, 2H),
7.56 (d, J=8.74 Hz, 2H), 7.88 (t, J=1.87 Hz, 1H), 8.87 (s, 1H),
8.92 (s, 1H).
Example 62
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 58B and 1-isocyanato-3-ethylbenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 402 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.19 (t, J=7.64 Hz, 3H), 2.58 (q, J=7.70 Hz,
2H), 3.94 (s, 3H), 6.73 (d, J=7.49 Hz, 1H), 6.82 (t, J=7.80 Hz,
2H), 7.19 (t, J=7.80 Hz, 1H), 7.27 (d, J=7.80 Hz, 1H), 7.34 (s,
1H), 7.35 (d, J=8.42 Hz, 2H), 7.56 (d, J=8.42 Hz, 2H), 8.64 (s,
1H), 8.75 (s, 1H).
Example 63
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylpheny-
l)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 58B and 2-fluoro-4-isocyanato-1-methylbenzene
for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 406 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 2.17 (s, 3H), 3.94 (s, 3H), 6.75 (d, J=7.49
Hz, 1H), 6.83 (d, J=7.80 Hz, 1H), 7.05 (dd, J=8.27, 2.03 Hz, 1H),
7.17 (t, J=8.58 Hz, 1H), 7.36 (d, J=8.73 Hz, 2H), 7.45 (dd,
J=12.48, 1.87 Hz, 1H), 7.56 (d, J=8.73 Hz, 2H), 8.82 (s, 1H), 8.83
(s, 1H).
Example 64
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluorom-
ethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 58B and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 460 (M+H).sup.+; NMR (500 MHz, DMSO-d.sub.6) .delta.
3.95 (s, 3H), 6.79 (d, J=7.80 Hz, 1H), 6.86 (d, J=7.80 Hz, 1H),
7.38 (d, J=8.42 Hz, 2H), 7.44 (t, J=9.67 Hz, 1H), 7.59 (d, J=8.73
Hz, 2H), 7.67 (dt, J=8.66, 3.78 Hz, 1H), 8.03 (dd, J=6.40, 2.65 Hz,
1H), 9.01 (s, 1H), 9.17 (s, 1H).
Example 65
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 58B and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 408 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.94 (s, 3H), 6.76 (d, J=7.49 Hz, 1H), 6.84
(d, J=7.80 Hz, 1H), 7.02 (dt, J=6.63, 2.14 Hz, 1H), 7.31 (m, 2H),
7.37 (d, J=8.74 Hz, 2H), 7.57 (d, J=8.42 Hz, 2H), 7.74 (m, 1H),
8.90 (s, 1H), 8.96 (s, 1H).
Example 66
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phe-
nyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 58B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 442 (M+H).sup.+; NMR (500 MHz, DMSO-d.sub.6) .delta.
3.94 (s, 3H), 6.76 (d, J=7.80 Hz, 1H), 6.84 (d, J=7.80 Hz, 1H),
7.32 (d, J=7.80 Hz, 1H), 7.38 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95
Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 7.57-7.61 (m, 1H), 8.04 (s, 1H),
8.96 (s, 1H), 9.14 (s, 1H).
Example 67
N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 58B for Example 15G in Example 15H. MS
(ESI(+)) m/e 392 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.94 (s, 3H), 6.77 (d, J=7.80 Hz, 1H), 6.77-6.81 (m, 1H),
6.85 (d, J=7.80 Hz, 1H), 7.14 (dd, J=8.11, 0.94 Hz, 1H), 7.29-7.34
(m, 1H), 7.37 (d, J=8.73 Hz, 2H), 7.51 (dt, J=11.93, 2.30 Hz, 1H),
7.57 (d, J=8.73 Hz, 2H), 8.89 (s, 1H), 8.98 (s, 1H).
Example 68
N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-methylphen-
yl)urea
Example 68A
2-fluoro-3-hydroxy-6-iodobenzonitrile
A -78.degree. C. solution of 2-fluoro-6-iodo-3-methoxybenzonitrile
(148 mg, 0.53 mmol) in dichloromethane (5 mL) was treated dropwise
with BBr.sub.3 (2.5 mL, 1M in dichloromethane, 2.5 mmol), warmed to
room temperature, stirred for 18 hours, poured into water, and
extracted with diethyl ether. The extract was dried (MgSO.sub.4),
filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel with 20% ethyl acetate/hexanes
to provide 110 mg of the desired product. MS (ESI(-)) m/e 262
(M-H).sup.-.
Example 68B
2-fluoro-6-iodo-3-(2-methoxyethoxy)benzonitrile
A mixture of Example 68A (104 mg, 0.39 mmol),
1-bromo-2-methoxyethane (0.088 mL) and K.sub.2CO.sub.3 (163 mg) in
acetone (3 mL) was heated to 60.degree. C. for 18 hours, cooled to
room temperature, and partitioned between diethyl ether and water.
The extract was dried (MgSO.sub.4), filtered, and concentrated to
provide 122 mg of the desired product. MS (ESI(+)) m/e 334
(M+H).sup.+.
Example 68C
4-(4-aminophenyl)-7-(2-methoxyethoxy)-1H-indazol-3-amine
The desired product was prepared by substituting Example 68B for
Example 15E in Examples 15F-G. MS (ESI(+)) m/e 299 (M+H).sup.+.
Example 68D
N-{-4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-methylphe-
nyl)urea
The desired product was prepared by substituting Example 68C and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15, then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 432
(M+H).sup.+; NMR (300 MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 3.35
(s, 3H), 3.76 (dd, J=5.09, 3.73 Hz, 2H), 4.27 (t, J=3.05 Hz, 2H),
4.29 (s, 2H), 6.67 (d, J=7.46 Hz, 1H), 6.79 (d, J=7.80 Hz, 2H),
7.16 (t, J=7.63 Hz, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d,
J=8.48 Hz, 2H), 7.55 (d, J=8.48 Hz, 2H), 8.63 (s, 1H), 8.76 (s,
1H), 11.83 (s, 1H).
Example 69
N-{-4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-phenylurea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 68C and isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 418 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 3.36 (s, 3H), 3.76 (t, J=4.41 Hz, 2H), 4.30 (t, J=4.75 Hz,
2H), 6.74 (d, J=7.80 Hz, 1H), 6.86 (d, J=7.80 Hz, 1H), 6.98 (t,
J=7.29 Hz, 1H), 7.29 (t, J=7.46 Hz, 2H), 7.36 (d, J=8.82 Hz, 2H),
7.47 (d, J=7.46 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 8.72 (s, 1H),
8.80 (s, 1H).
Example 70
N-{-4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-fluorophe-
nyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 68C for Example 15G in Example 15H. MS
(ESI(+)) m/e 436 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.36 (s, 3H), 3.75-3.77 (m, 2H), 4.28-4.30 (m, 2H), 6.73
(d, J=7.80 Hz, 1H), 6.79 (td, J=8.58, 2.18 Hz, 1H), 6.85 (d, J=7.80
Hz, 1H), 7.14 (dd, J=8.27, 1.09 Hz, 1H), 7.31 (m, 1H), 7.37 (d,
J=8.74 Hz, 2H), 7.51 (dt, J=11.93, 2.30 Hz, 1H), 7.57 (d, J=8.42
Hz, 2H), 8.89 (s, 1H), 8.98 (s, 1H).
Example 71
N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-bromopheny-
l)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 68C and 1-bromo-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 496 and 498 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 3.36 (s, 3H), 3.75-3.77 (m, 2H),
4.28-4.30 (m, 2H), 6.73 (d, J=7.49 Hz, 1H), 6.84 (d, J=7.80 Hz,
1H), 7.16 (d, J=7.80 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H), 7.33 (dd,
J=8.27, 1.09 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.57 (d, J=8.42 Hz,
2H), 7.88 (t, J=1.87 Hz, 1H), 8.87 (s, 1H), 8.92 (s, 1H).
Example 72
N-{-4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlorophe-
nyl)urea
The desired product was prepared by as the trifluoroacetate salt
substituting Example 68C and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 452 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.36 (s, 3H), 3.76 (t, J=4.68 Hz, 2H), 4.29
(t, J=4.68 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.85 (d, J=7.80 Hz,
1H), 7.02 (dt, J=6.86, 2.03 Hz, 1H), 7.30 (m, 2H), 7.37 (d, J=8.42
Hz, 2H), 7.57 (d, J=8.42 Hz, 2H), 7.73 (s, 1H), 8.89 (s, 1H), 8.95
(s, 1H).
Example 73
N-{-4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(trifluor-
omethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 68C and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 486 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.36 (s, 3H), 3.75-3.77 (m, 2H), 4.29-4.31 (m, 2H), 6.75
(d, J=7.80 Hz, 1H), 6.86 (d, J=7.80 Hz, 1H), 7.32 (d, J=8.11 Hz,
1H), 7.38 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95 Hz, 1H), 7.59 (d,
J=8.42 Hz, 2H), 7.58-7.61 (m, 1H), 8.04 (s, 1H), 8.95 (s, 1H), 9.12
(s, 1H).
Example 74
N-{-4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-[2-fluoro-5--
(trifluoromethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 68C and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 504 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.36 (s, 3H), 3.76 (t, J=4.68 Hz, 2H), 4.29 (t, J=4.68 Hz,
2H), 6.73 (d, J=7.80 Hz, 1H), 6.85 (d, J=7.80 Hz, 1H), 7.39 (d,
J=8.74 Hz, 2H), 7.39-7.41 (m, 1H), 7.51 (m, 1H), 7.58 (d, J=8.42
Hz, 2H), 8.64 (dd, J=7.18, 2.18 Hz, 1H), 8.93 (d, J=2.81 Hz, 1H),
9.28 (s, 1H).
Example 75
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-me-
thylphenyl)urea
Example 75A
2-fluoro-6-iodo-3-[2-(4-morpholinyl)ethoxy]benzonitrile
A mixture of Example 68A (250 mg, 0.95 mmol),
2-(4-morpholinyl)ethanol (0.19 mL) and triphenylphosphine on resin
(630 mg, 3 mmol/g, 1.9 mmol) in THF (5 mL) was treated with DEAD
(0.179 mL) and stirred at room temperature for about 18 hours. The
mixture was filtered and the filtrate was concentrated. The residue
was purified twice by flash column chromatography on silica gel,
first eluting with 5% methanol/dichloromethane then with 50% ethyl
acetate/hexanes to provide 180 mg of the desired product. MS
(ESI(+)) m/e 377 (M+H).sup.+.
Example 75B
4-(4-aminophenyl)-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-3-amine
The desired product was prepared by substituting Example 75A for
Example 15E in Examples 15F-G. MS (ESI(+)) m/e 354 (M+H).sup.+.
Example 75C
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-me-
thylphenyl)urea
The desired product was prepared by substituting Example 75B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 487
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.29 (s,
3H), 2.52-2.55 (m, 4H), 2.79 (t, J=5.76 Hz, 2H), 3.57-3.60 (m, 4H),
4.26 (t, J=5.76 Hz, 2H), 4.30 (s, 2H), 6.68 (d, J=7.46 Hz, 1H),
6.80 (d, J=7.80 Hz, 2H), 7.16 (t, J=7.80 Hz, 1H), 7.25 (m, 1H),
7.31 (s, 1H), 7.34 (d, J=8.48 Hz, 2H), 7.55 (d, J=8.82 Hz, 2H),
8.64 (s, 1H), 8.77 (s, 1H), 11.81 (s, 1H).
Example 76
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-pheny-
lurea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B and isocyanatobenzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 473 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.66 (m, 2H), 3.33-4.45 (br m, 8H), 4.54 (m, 2H), 6.75 (d,
J=7.80 Hz, 1H), 6.90 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.33 Hz, 1H),
7.29 (t, J=7.80 Hz, 2H), 7.36 (d, J=8.73 Hz, 2H), 7.48 (d, J=7.49
Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 8.86 (s, 1H), 8.95 (s, 1H).
Example 77
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-fl-
uorophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B for Example 15G in Example 15H. MS
(ESI(+)) m/e 491 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.66 (t, J=4.37 Hz, 2H), 3.71 (br m, 8H), 4.53 (t, J=4.99
Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.79 (td, J=8.42, 1.87 Hz, 1H),
6.89 (d, J=7.80 Hz, 1H), 7.15 (dd, J=8.27, 1.09 Hz, 1H), 7.31 (m,
1H), 7.36 (d, J=8.74 Hz, 2H), 7.52 (dt, J=12.09, 2.22 Hz, 1H), 7.58
(d, J=8.74 Hz, 2H), 8.97 (s, 1H), 9.06 (s, 1H).
Example 78
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-br-
omophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B and 1-bromo-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 551 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.66 (t, J=4.36 Hz, 2H), 3.30-4.32 (br m,
8H), 4.54 (t, J=4.68 Hz, 2H), 6.75 (d, J=7.49 Hz, 1H), 6.89 (d,
J=7.80 Hz, 1H), 7.16 (d, J=8.73 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H),
7.34-7.35 (m, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.42 Hz,
2H), 7.89 (t, J=1.87 Hz, 1H), 9.07 (s, 1H), 9.11 (s, 1H).
Example 79
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-et-
hylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B and 1-ethyl-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 501 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.19 (t, J=7.49 Hz, 3H), 2.58 (q, J=7.49 Hz,
2H), 3.66 (m, 2H), 3.31-4.01 (br m, 8H), 4.53 (m, 2H), 6.74 (d,
J=7.80 Hz, 1H), 6.83 (d, J=7.49 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H),
7.19 (t, J=7.80 Hz, 1H), 7.27 (d, J=8.42 Hz, 1H), 7.35 (m, J=8.42
Hz, 3H), 7.58 (d, J=8.73 Hz, 2H), 8.70 (s, 1H), 8.82 (s, 1H).
Example 80
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[2-fl-
uoro-5-(trifluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(-)) m/e 557 (M-H).sup.-; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.66 (t, J=4.68 Hz, 2H), 3.32-4.20 (br m, 8H), 4.54 (t,
J=4.68 Hz, 2H), 6.76 (d, J=7.49 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H),
7.39 (d, J=8.73 Hz, 2H), 7.41 (m, J=4.06 Hz, 1H), 7.51 (t, J=8.73
Hz, 1H), 7.59 (d, J=8.73 Hz, 2H), 8.64 (dd, J=7.33, 2.03 Hz, 1H),
8.97 (d, J=2.81 Hz, 1H), 9.34 (s, 1H).
Example 81
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[4-fl-
uoro-3-(trifluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(-)) m/e 557 (M-H); NMR (500 MHz, DMSO-d.sub.6) .delta. 3.66
(m, 2H), 3.83 (m, 8H), 4.53 (m, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.89
(d, J=7.80 Hz, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.45 (t, J=9.67 Hz,
1H), 7.59 (d, J=8.73 Hz, 2H), 7.66 (dt, J=8.74, 3.74 Hz, 1H), 8.04
(dd, J=6.40, 2.65 Hz, 1H), 9.08 (s, 1H), 9.25 (s, 1H).
Example 82
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-ch-
lorophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 507 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 3.31-4.00 (br m, 8H), 3.65 (m, 2H), 4.53 (m,
2H), 6.75 (d, J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.01 (td,
J=4.45, 2.03 Hz, 1H), 7.30 (d, J=4.99 Hz, 2H), 7.35 (d, J=8.42 Hz,
2H), 7.58 (d, J=8.42 Hz, 2H), 7.73 (s, 1H), 9.10 (s, 1H), 9.15 (s,
1H).
Example 83
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(t-
rifluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(-)) m/e 539 (M-H).sup.-; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.66 (m, 2H), 3.32-4.11 (m, 8H), 4.54 (m, 2H), 6.75 (d,
J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.31 (d, J=7.80 Hz, 1H),
7.37 (d, J=8.42 Hz, 2H), 7.52 (s, 1H), 7.61 (d, J=8.42 Hz, 2H),
7.62 (m, 1H), 8.06 (s, 1H), 9.18 (s, 1H), 9.36 (s, 1H).
Example 84
(2E)-3-{3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-in-
dazol-7-yl}-N,N-dimethylacrylamide
Example 84A
7-bromo-4-iodo-1H-indazol-3-amine
The desired product was prepared by substituting
4-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile
in Example 1A.
Example 84B
7-bromo-4-(4-nitrophenyl)-1H-indazol-3-amine
The desired product was prepared by substituting Example 84A and
4-nitrophenylboronic acid for Example 1A and Example 1B,
respectively, in Example 1C. MS (ESI(+)) m/e 333, 335
(M+H).sup.+.
Example 84C
(2E)-3-[3-amino-4-(4-nitrophenyl)-1H-indazol-7-yl]-N,N-dimethylacrylamide
A mixture of Example 84B (165 mg), N,N-dimethylacrylamide (0.102
mL), triethylamine (0.207 mL), and Pd(o-tol.sub.3P).sub.2Cl.sub.2
(30 mg) in THF (2 mL) in a sealed tube was heated in a Smith
Synthesizer microwave oven (at 300 W) to 150.degree. C. and
concentrated. The residue was purified by flash column
chromatography on silica gel with 3% methanol/dichloromethane to
provide 163 mg of the desired product. MS (ESI(+)) m/e 352
(M-H).sup.+.
Example 84D
(2E)-3-[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]-N,N-dimethylacrylamide
A solution of Example 84C (113 mg, 0.32 mmol) in a mixture of
ethanol (1 mL), methanol (1 mL), and THF (1 mL) was treated with
iron powder (144 mg) and NH.sub.4Cl (17 mg), heated to 85.degree.
C. for 4 hours, cooled to room temperature, and filtered. The
filtrate was partitioned between water and ethyl acetate and the
organic phase was dried (MgSO.sub.4), filtered, and concentrated.
The residue was purified by flash column chromatography on silica
gel with 5% methanol/dichloromethane to provide 75 mg of the
desired product. MS (ESI(+)) m/e 322 (M+H).sup.+.
Example 84E
(2E)-3-{3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-in-
dazol-7-yl}-N,N-dimethylacrylamide
The desired product was prepared as the trifluoroacetate salt by
substituting Example 84D and 1-isocyanato-3-methylbenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 455 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.28 (s, 3H), 2.97 (s, 3H), 3.21 (s, 3H),
6.80 (d, J=8.14 Hz, 1H), 6.86 (d, J=7.46 Hz, 1H), 7.17 (m, 1H),
7.24 (m, 2H), 7.32 (s, 1H), 7.41 (d, J=8.82 Hz, 2H), 7.61 (d,
J=8.81 Hz, 2H), 7.70 (d, J=7.80 Hz, 1H), 7.85 (d, J=15.60 Hz, 1H),
8.65 (s, 1H), 8.83 (s, 1H).
Example 85
(2E)-3-{3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-in-
dazol-7-yl}-N,N-dimethylacrylamide
The desired product was prepared by substituting Example 84D and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 475
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.97 (s,
3H), 3.21 (s, 3H), 4.44 (s, 2H), 6.86 (d, J=7.46 Hz, 1H), 7.01-7.06
(m, 1H), 7.23 (d, J=15.60 Hz, 1H), 7.30-7.32 (m, 2H), 7.43 (d,
J=8.48 Hz, 2H), 7.61 (d, J=8.82 Hz, 2H), 7.70 (d, J=7.46 Hz, 1H),
7.74 (m, 1H), 7.85 (d, J=15.60 Hz, 1H), 8.96 (s, 1H), 8.98 (s, 1H),
12.17 (s, 1H).
Example 86
(2E)-3-(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]ph-
enyl}-1H-indazol-7-yl)-N,N-dimethylacrylamide
The desired product was prepared by substituting Example 84D and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. MS (ESI(-)) m/e 507
(M-H).sup.-; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.97 (s,
3H), 3.21 (s, 3H), 4.44 (s, 2H), 6.86 (d, J=7.12 Hz, 1H), 7.23 (d,
J=15.60 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.43 (d, J=8.48 Hz, 2H),
7.53 (t, J=7.97 Hz, 1H), 7.59 (s, 1H), 7.63 (d, J=8.81 Hz, 2H),
7.70 (d, J=7.80 Hz, 1H), 7.85 (d, J=15.26 Hz, 1H), 8.04 (s, 1H),
8.99 (s, 1H), 9.13 (s, 1H), 12.17 (s, 1H).
Example 87
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-pheny-
lurea
Example 87A
4-(4-aminophenyl)-7-[2-(dimethylamino)ethoxy]-1H-indazol-3-amine
The desired product was prepared by substituting
2-(dimethylamino)ethanol for 2-(4-morpholinyl)ethanol in Example
75A-B. MS (ESI(+)) m/e 312 (M+H).sup.+.
Example 87B
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-pheny-
lurea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 87A and isocyanatobenzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 431 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 2.95 (s, 6H), 3.61 (br s, 2H), 4.49 (m, 2H), 6.77 (d,
J=7.63 Hz, 1H), 6.90 (d, J=7.63 Hz, 1H), 6.98 (t, J=7.32 Hz, 1H),
7.29 (t, J=7.93 Hz, 2H), 7.36 (d, J=8.54 Hz, 2H), 7.48 (d, J=7.93
Hz, 2H), 7.59 (d, J=8.54 Hz, 2H), 8.88 (s, 1H), 8.97 (s, 1H).
Example 88
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-br-
omophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 87A and 1-bromo-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 509 and 511 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 2.95 (s, 6H), 3.61 (s, 2H), 4.50
(m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.63 Hz, 1H), 7.16 (d,
J=8.85 Hz, 1H), 7.25 (t, J=8.09 Hz, 1H), 7.35 (m, J=10.68 Hz, 1H),
7.37 (d, J=8.54 Hz, 2H), 7.60 (d, J=8.54 Hz, 2H), 7.90 (t, J=1.83
Hz, 1H), 9.17 (s, 1H), 9.21 (s, 1H).
Example 89
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-me-
thylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 87A and 1-isocyanato-3-methylbenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 445 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 2.29 (s, 3H), 2.95 (s, 6H), 3.61 (br s, 2H),
4.50 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.80 (d, J=7.32 Hz, 1H),
6.90 (d, J=7.63 Hz, 1H), 7.16 (t, J=7.78 Hz, 1H), 7.26 (d, J=8.54
Hz, 1H), 7.33 (s, 1H), 7.36 (d, J=8.54 Hz, 2H), 7.59 (d, J=8.54 Hz,
2H), 8.81 (s, 1H), 8.97 (s, 1H).
Example 90
N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-ch-
lorophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 87A and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(-)) m/e 463 (M-H).sup.-; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 2.95 (s, 6H), 3.61 (br s, 2H), 4.50 (m, 2H),
6.77 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.93 Hz, 1H), 7.02 (td, J=4.42,
2.14 Hz, 1H), 7.31 (m, 2H), 7.37 (d, J=8.85 Hz, 2H), 7.60 (d,
J=8.54 Hz, 2H), 7.75 (s, 1H), 9.14 (s, 1H), 9.20 (s, 1H).
Example 91
N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-
'-(3-methylphenyl)urea
Example 91A
1-(2-{[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]oxy}ethyl)-2-pyrrolidinon-
e
The desired product was prepared by substituting
1-(2-hydroxyethyl)-2-pyrrolidinone for 2-(4-morpholinyl)ethanol in
Example 75A-B. MS (ESI(+)) m/e 352 (M+H).sup.+.
Example 91B
N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-
'-(3-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 91A and 1-isocyanato-3-methylbenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 485 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.93 (m, 2H), 2.24 (t, J=8.14 Hz, 2H), 2.29
(s, 3H), 3.55 (m, 2H), 3.62 (m, 2H), 4.27 (t, J=5.43 Hz, 2H), 6.73
(d, J=7.80 Hz, 1H), 6.80 (d, J=7.12 Hz, 1H), 6.86 (d, J=7.80 Hz,
1H), 7.16 (t, J=7.80 Hz, 1H), 7.25 (m, 1H), 7.32 (s, 1H), 7.35 (d,
J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.64 (s, 1H), 8.78 (s,
1H).
Example 92
2-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide
The desired product was prepared by substituting Example 34A and
2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-N-m-tolyl-ace-
tamide for Example 1A and Example 1B, respectively, in Example 53C.
The crude product was purified by preparative HPLC using the
conditions described in Example 3 to provide the desired product as
the trifluoroacetate salt. MS (ESI(+)) m/e 371 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 2.27 (s, 3H), 3.72 (s, 2H),
3.80 (s, 3H), 6.82 (dd, J=6.61, 1.19 Hz, 1H), 6.86 (d, J=7.46 Hz,
1H), 7.18 (t, J=7.80 Hz, 1H), 7.31-7.48 (m, 8H), 10.13 (s, 1H).
Example 93
N-[4-(3-amino-1H-indazol-4-yl)-2-methylphenyl]-N'-(3-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting 4-bromo-2-methylaniline for 4-bromo-2-fluoroaniline in
Example 44A-B. MS (ESI(-)) m/e 370 (M-H).sup.-; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 2.33 (s, 3H), 6.80 (d,
J=7.46 Hz, 1H), 6.85 (dd, J=6.10, 1.70 Hz, 1H), 7.17 (t, J=7.80 Hz,
1H), 7.25-7.34 (m, 6H), 8.03 (m, 2H), 9.03 (s, 1H).
Example 94
N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N-
'-(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 91A and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 505 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.93 (m, 2H), 2.24 (t, J=8.14 Hz, 2H), 3.55
(m, 2H), 3.62 (t, J=5.43 Hz, 2H), 4.27 (t, J=5.59 Hz, 2H), 6.74 (d,
J=7.80 Hz, 1H), 6.87 (d, J=8.14 Hz, 1H), 7.03 (dt, J=6.53, 2.33 Hz,
1H), 7.30 (s, 1H), 7.31 (d, J=3.73 Hz, 1H), 7.37 (d, J=8.48 Hz,
2H), 7.57 (d, J=8.48 Hz, 2H), 7.74 (d, J=1.70 Hz, 1H), 8.89 (s,
1H), 8.95 (s, 1H).
Example 95
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
Example 95A
4-bromo-1,2-benzisoxazol-3-amine
A suspension of acetylhydroxamic acid (2.46 g, 32.8 mmol) and
potassium tert-butoxide (3.68 g, 32.8 mmol) in DMF (40 mL) was
stirred at room temperature for 30 minutes, treated with
2-bromo-6-fluorobenzonitrile (4.36 g, 21.8 mmol), stirred for three
hours, poured into water, and extracted three times with ethyl
acetate. The combined extracts were washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was purified
by flash column chromatography on silica gel with 5 to 20% ethyl
acetate/hexanes to provide 2.5 g of the desired product. MS
(ESI(+)) m/e 212.9, 214.9 (M+H).sup.+.
Example 95B
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 95A for
Example 1A in Example 1C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.29 (s, 3H), 5.22 (s, 2H), 6.81 (d, J=7.12 Hz, 1H),
7.10-7.70 (m, 10H), 8.66 (s, 1H), 8.85 (s, 1H); MS (ESI(+)) m/e 359
(M+H).sup.+.
Example 96
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethyl)phenyl]-
urea
Example 96A
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[2-(trifluoro-
methyl)phenyl]urea
The desired product was prepared by substituting
1-isocyanato-2-(trifluoromethyl)benzene for
1-isocyanato-3-methylbenzene in Example 1B.
Example 96B
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethyl)phenyl]-
urea
The desired product was prepared by substituting Example 95A and
Example 96A for Example 1A and Example 1B, respectively, in Example
1C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.22 (s, 2H),
7.00-7.75 (m, 10H), 7.95 (d, J=7.80 Hz, 1H), 8.16 (s, 1H), 9.57 (s,
1H); MS (ESI(+)) m/e 413 (M+H).sup.+.
Example 97
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)ur-
ea
The desired product was prepared by substituting Example 95A and
Example 5A for Example 1A and Example 1B, respectively, in Example
1C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 5.22
(s, 2H), 6.75-6.85 (m, 1H), 7.06-7.18 (m, 2H), 7.40-7.66 (m, 6H),
8.00 (dd, J=7.97, 1.86 Hz, 1H), 8.55 (d, J=2.37 Hz, 1H), 9.25 (s,
1H); MS (ESI(+)) m/e 377 (M+H).sup.+.
Example 98
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]-
urea
Example 98A
N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-[3-(trifluoro-
methyl)phenyl]urea
The desired product was prepared by substituting
1-isocyanato-3-(trifluoromethyl)benzene for
1-isocyanato-3-methylbenzene in Example 1B.
Example 98B
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]-
urea
The desired product was prepared by substituting Example 95A and
Example 98A for Example 1A and Example 1B, respectively, in Example
1C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.22 (s, 2H), 7.14
(d, J=6.78 Hz, 1H), 7.33 (d, J=7.12 Hz, 1H), 7.40-7.75 (m, 8H),
8.04 (s, 1H), 9.00 (s, 1H), 9.12 (s, 1H); MS (ESI(+)) m/e 413
(M+H).sup.+.
Example 99
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethy-
l)phenyl]urea
Example 99A
N-[2-fluoro-5-(trifluoromethyl)phenyl]-N'-[4-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)phenyl]urea
The desired product was prepared by substituting
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for
1-isocyanato-3-methylbenzene in Example 1B.
Example 99B
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluoromethy-
l)phenyl]urea
The desired product was prepared by substituting Example 95A and
Example 99A for Example 1A and Example 1B, respectively, in Example
1C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.22 (s, 2H), 7.15
(d, J=7.12 Hz, 1H), 7.40-7.70 (m, 8H), 8.64 (d, J=7.46 Hz, 1H),
8.98 (s, 1H), 9.38 (s, 1H); MS (ESI(+)) m/e 431 (M+H).sup.+.
Example 100
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trif-
luoromethyl)phenyl]urea
Example 100A
2-fluoro-6-iodo-3-methoxybenzonitrile
The desired product was prepared by substituting
2-fluoro-4-iodo-1-methoxybenzene for
2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.
Example 100B
4-iodo-7-methoxy-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 100A for
2-bromo-6-fluorobenzonitrile in Example 95A.
Example 100C
4-(4-aminophenyl)-7-methoxy-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 100B for
Example 15F in Example 15G. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 3.93 (s, 3H), 5.19 (s, 2H), 531 (s, 2H), 6.67 (d, J=8.48
Hz, 2H), 6.94 (d, J=8.14 Hz, 1H), 7.10 (m, 3H); MS (ESI(+)) ink
256.0 (M+H).sup.+.
Example 100D
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N-[2-fluoro-5-(trifl-
uoromethyl)phenyl]urea
The desired product was prepared by substituting Example 100C and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 3.97 (s, 3H), 5.21 (s, 2H), 7.05
(d, J=8.14 Hz, 1H), 7.17 (d, J=8.14 Hz, 1H), 7.41 (d, J=8.82 Hz,
3H), 7.45-7.56 (m, 1H), 7.61 (d, J=8.48 Hz, 2H), 8.64 (dd, J=7.12,
2.37 Hz, 1H), 8.96 (d, J=2.71 Hz, 1H), 9.34 (s, 1H); MS (ESI(+))
m/e 461 (M+H).sup.+.
Example 101
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)u-
rea
The desired product was prepared by substituting Example 100C and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 3.96 (s, 3H), 5.21
(s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.04 (d, J=8.14 Hz, 1H),
7.10-7.35 (m, 4H), 7.37 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.82 Hz,
2H), 8.64 (s, 1H), 8.81 (s, 1H); MS (ESI(+)) m/e 389
(M+H).sup.+.
Example 102
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluorometh-
yl)phenyl]urea
The desired product was prepared by substituting Example 100C and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 3.96 (s, 3H), 5.21 (s, 2H), 7.05
(d, J=7.80 Hz, 1H), 7.17 (d, J=8.14 Hz, 1H), 7.32 (d, J=7.46 Hz,
1H), 7.39 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.80 Hz, 1H), 7.61 (m,
3H), 8.04 (s, 1H), 8.96 (s, 1H), 9.10 (s, 1H); MS (ESI(+)) m/e
443.0 (M+H).sup.+.
Example 103
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)u-
rea
The desired product was prepared by substituting Example 100C and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 3.96 (s, 3H), 5.20 (s, 2H),
7.00-7.06 (m, 2H), 7.16 (d, J=8.14 Hz, 1H), 7.25-7.35 (m, 2H), 7.39
(d, J=8.81 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H), 7.73 (t, J=2.03 Hz,
1H), 8.92 (s, 1H), 8.94 (s, 1H); MS (ESI(+)) m/e 409
(M+H).sup.+.
Example 104
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methy-
lphenyl)urea
The desired product was prepared by substituting Example 100C and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 3.96 (s, 3H), 5.21
(s, 2H), 6.75-6.90 (m, 1H), 7.00-7.20 (m, 3H), 7.39 (d, J=8.81 Hz,
2H), 7.59 (d, J=8.48 Hz, 2H), 8.00 (dd, J=7.63, 1.86 Hz, 1H), 8.53
(d, J=2.37 Hz, 1H), 9.22 (s, 1H); MS (ESI(+)) m/e 407.0
(M+H).sup.+.
Example 105
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-
-fluoro-5-(trifluoromethyl)phenyl]urea
Example 105A
4-iodo-7-(4-morpholinylmethyl)-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 15E for
2-bromo-6-fluorobenzonitrile in Example 95A.
Example 105B
4-(4-aminophenyl)-7-(4-morpholinylmethyl)-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 105A for
Example 15F in Example 15G. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.38-2.45 (m, 4H), 3.55-3.63 (m, 4H), 3.70 (s, 2H), 5.21
(s, 2H), 5.38 (s, 2H), 6.69 (d, J=8.48 Hz, 2H), 7.02 (d, J=7.46 Hz,
1H), 7.15 (d, J=8.48 Hz, 2H), 7.45 (d, J=7.46 Hz, 1H).
Example 105C
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2--
fluoro-5-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 105B and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.44 (s, 4H), 3.59 (s, 4H), 3.74
(s, 2H), 5.23 (s, 2H), 7.13 (d, J=7.46 Hz, 1H), 7.35-7.55 (m, 5H),
7.64 (d, J=8.81 Hz, 2H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.99 (d,
J=2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI(+)) m/e 530 (M+H).sup.+.
Example 106
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3-
-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 105B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, CF.sub.3CO.sub.2D) .delta. 2.44 (s, 4H), 3.59 (s, 4H),
3.74 (s, 2H), 5.23 (s, 2H), 7.12 (d, J=7.46 Hz, 1H), 7.33 (d,
J=7.46 Hz, 1H), 7.44 (d, J=8.48 Hz, 2H), 7.50-7.68 (m, 5H), 8.04
(s, 1H), 9.04 (s, 1H), 9.16 (s, 1H); MS (ESI(+)) m/e 512
(M+H).sup.+.
Example 107
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3--
chlorophenyl)urea
The desired product was prepared by substituting Example 105B and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.44 (s, 4H), 3.59 (s, 4H), 3.73
(s, 2H), 5.22 (s, 2H), 6.95-7.06 (m, 1H), 7.12 (d, J=7.46 Hz, 1H),
7.25-7.38 (m, 2H), 7.44 (d, J=8.48 Hz, 2H), 7.52 (d, J=7.80 Hz,
1H), 7.62 (d, J=8.48 Hz, 2H), 7.70-7.78 (m, 1H), 8.99 (s, 2H); MS
(ESI(+)) m/e 478 (M+H).sup.+.
Example 108
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3--
methylphenyl)urea
The desired product was prepared by substituting Example 105B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 2.44 (s, 4H), 3.59
(s, 4H), 3.73 (s, 2H), 5.23 (s, 2H), 6.80 (d, J=7.80 Hz, 1H),
7.05-7.35 (m, 5H), 7.42 (d, J=8.48 Hz, 1H), 7.52 (d, J=7.12 Hz,
1H), 7.62 (d, J=8.48 Hz, 2H), 8.67 (s, 1H), 8.86 (s, 1H); MS
(ESI(+)) m/e 458 (M+H).sup.+.
Example 109
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(2--
fluoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 105B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 2.35-2.48 (m, 4H),
3.50-3.65 (m, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 6.75-6.85 (m, J=2.37
Hz, 1H), 7.05-7.18 (m, 2H), 7.44 (d, J=8.48 Hz, 2H), 7.52 (d,
J=7.80 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H), 8.00 (dd, J=7.80, 1.70 Hz,
1H), 8.55 (d, J=2.37 Hz, 1H), 9.25 (s, 1H); MS (ESI(+)) m/e 476
(M+H).sup.+.
Example 110
N-{-4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-
,5-dimethylphenyl)urea
The desired product was prepared by substituting Example 105B and
1-isocyanato-3,5-dimethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.24 (s, 6H), 2.44 (s, 4H), 3.59
(s, 4H), 3.73 (s, 2H), 5.23 (s, 2H), 6.63 (s, 1H), 7.05-7.15 (m,
3H), 7.42 (d, J=8.48 Hz, 2H), 7.52 (d, J=7.46 Hz, 1H), 7.61 (d,
J=8.81 Hz, 2H), 8.59 (s, 1H), 8.84 (s, 1H); MS (ESI(+)) m/e 472
(M+H).sup.+.
Example 111
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3--
phenoxyphenyl)urea
The desired product was prepared by substituting Example 105B and
1-isocyanato-3-phenoxybenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.40-2.48 (m, 4H), 3.55-3.64 (m,
4H), 3.73 (s, 2H), 5.21 (s, 2H), 6.60-6.68 (m, 1H), 7.00-7.20 (m,
5H), 7.25-7.32 (m, 2H), 7.35-7.45 (m, 4H), 7.51 (d, J=7.46 Hz, 1H),
7.59 (d, J=8.82 Hz, 2H), 8.84 (s, 1H), 8.87 (s, 1H); MS (ESI(+))
m/e 536.1 (M+H).sup.+.
Example 112
N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3--
bromophenyl)urea
The desired product was prepared by substituting Example 105B and
1-bromo-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.40-2.48 (m, 4H), 3.50-3.65 (m, 4H), 3.73
(s, 2H), 5.22 (s, 2H), 7.10-7.35 (m, 4H), 7.43 (d, J=8.48 Hz, 2H),
7.52 (d, J=7.46 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H), 7.88 (t, J=1.86
Hz, 1H), 8.96 (s, 2H); MS (ESI(+)) m/e 524 (M+H).sup.+.
Example 113
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-
-[3-(trifluoromethyl)phenyl]urea
Example 113A
4-iodo-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 75A for
2-bromo-6-fluorobenzonitrile in Example 95A.
Example 113B
4-(4-aminophenyl)-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 113A for
Example 15F in Example 15G. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.45-2.60 (m, 4H), 2.76 (t, J=5.59 Hz, 2H), 3.50-3.70 (m,
4H), 4.28 (t, J=5.59 Hz, 2H), 5.19 (s, 2H), 5.31 (s, 2H), 6.67 (d,
J=8.48 Hz, 2H), 6.92 (d, J=7.80 Hz, 1H), 7.05-7.18 (m, 3H); MS
(ESI(+)) m/e 355.0 (M+H).sup.+.
Example 113C
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-
-[3-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 113B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.45-2.60 (m, 4H), 2.78 (t, J=5.59
Hz, 2H), 3.50-3.65 (m, 4H), 4.31 (t, J=5.59 Hz, 2H), 5.21 (s, 2H),
7.03 (d, J=8.14 Hz, 1H), 7.19 (d, J=8.14 Hz, 1H), 7.32 (d, J=7.46
Hz, 1H), 7.39 (d, J=8.81 Hz, 2H), 7.53 (t, J=7.80 Hz, 1H),
7.57-7.66 (m, 3H), 8.04 (s, 1H), 8.96 (s, 1H), 9.10 (s, 1H); MS
(ESI(+)) m/e 542.1, 540.1.
Example 114
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-
-(2-fluoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 113B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 2.45-2.55 (m, 4H),
2.78 (t, J=5.59 Hz, 2H), 3.50-3.65 (m, 4H), 4.31 (t, J=5.76 Hz,
2H), 5.21 (s, 2H), 6.75-6.84 (m, 1H), 7.03 (d, J=8.14 Hz, 1H), 7.11
(dd, J=11.36, 8.31 Hz, 1H), 7.19 (d, J=8.14 Hz, 1H), 7.39 (d,
J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.00 (dd, J=7.80, 2.03 Hz,
1H), 8.53 (d, J=2.37 Hz, 1H), 9.22 (s, 1H); MS (ESI(+)) m/e 506.1
(M+H).sup.+.
Example 115
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-
-[2-fluoro-5-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 113B and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.45-2.55 (m, 4H), 2.78 (t, J=5.26
Hz, 2H), 3.50-3.67 (m, 4H), 4.31 (t, J=5.09 Hz, 2H), 5.21 (s, 2H),
7.03 (d, J=7.80 Hz, 1H), 7.19 (d, J=7.80 Hz, 1H), 7.35-7.70 (m,
6H), 8.64 (dd, J=6.78, 1.36 Hz, 1H), 8.96 (d, J=2.37 Hz, 1H), 9.34
(s, 1H); MS (ESI(+)) m/e 560.1 (M+H).sup.+.
Example 116
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N'-
-(3-methylphenyl)urea
The desired product was prepared by substituting Example 113B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 2.45-2.55 (m, 4H),
2.78 (t, J=5.26 Hz, 2H), 3.50-3.70 (m, 4H), 4.31 (t, J=4.92 Hz,
2H), 5.21 (s, 2H), 6.80 (d, J=7.46 Hz, 1H), 7.02 (d, J=7.80 Hz,
1H), 7.10-7.30 (m, 4H), 7.37 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48
Hz, 2H), 8.66 (s, 1H), 8.83 (s, 1H); MS (ESI(+)) m/e 488
(M+H).sup.+.
Example 117
N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-m-
ethylphenyl)urea
The desired product was prepared by substituting Example 68C and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
crude suspension was filtered and the solid collected was washed
with dichloromethane to provide the desired product. MS (ESI(+))
ink 450 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
2.28 (s, 3H), 3.36 (s, 3H), 3.76 (t, J=4.75 Hz, 2H), 4.26-4.29, (m,
2H), 4.29 (s, 2H), 6.68 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.80 Hz,
1H), 6.82 (m, 1H), 7.11 (dd, J=11.53, 8.14 Hz, 1H), 7.36 (d, J=8.82
Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80, 2.03 Hz, 1H),
8.52 (d, J=2.37 Hz, 1H), 9.16 (s, 1H).
Example 118
N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fl-
uoro-5-methylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 75B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 505 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 2.28 (s, 3H), 2.73 (m, 2H), 3.71 (m, 6H), 4.04 (m, 2H),
4.53 (m, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.81 (m, 1H), 6.88 (d,
J=7.80 Hz, 1H), 7.12 (dd, J=11.36, 8.31 Hz, 1H), 7.36 (d, J=8.82
Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 8.01 (s, 1H), 8.52 (d, J=2.71 Hz,
1H), 9.18 (s, 1H).
Example 119
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-me-
thylphenyl)urea
Example 119A
2-fluoro-6-iodo-3-(methoxymethoxy)benzonitrile
A 0.degree. C. solution of Example 68A (250 mg, 0.95 mmol) in THF
(5 mL) at room temperature was treated with NaH (25 mg, 95%, 1.05
mmol), stirred for 5 minutes, treated with chloromethyl methyl
ether (0.108 mL, 1.4 mmol), stirred overnight, and partitioned
between water and ethyl acetate. The organic extract was washed
with brine, dried (MgSO.sub.4), filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel
with 2% ethyl acetate/hexanes to provide 0.21 g of the desired
product. R.sub.1=0.4 (10% ethyl acetate/hexanes).
Example 119B
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-5-me-
thylphenyl)urea
The desired product was prepared by substituting Example 119A and
1-fluoro-2-isocyanato-4-methylbenzene for
2-fluoro-6-iodobenzonitrile and 1-isocyanato-3-methylbenzene,
respectively, in Examples 1A-1C. MS (ESI(+)) m/e 436 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 3.46 (s,
3H), 4.33 (s, 2H), 5.34 (s, 2H), 6.69 (d, J=7.80 Hz, 1H), 6.78-6.83
(m, 1H), 6.92 (d, J=7.80 Hz, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H),
7.36 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80,
1.70 Hz, 1H), 8.52 (d, J=2.71 Hz, 1H), 9.17 (s, 1H), 11.90 (s,
1H).
Example 120
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylpheny-
l)urea
A mixture of Example 119B (90 mg) and a 1:1:1 mixture of 3N
HCl/methanol/THF (3 mL) was heated to 50.degree. C. for 3 hours,
concentrated to half its original volume, and partitioned between
saturated NaHCO.sub.3 and ethyl acetate. The organic extract was
dried (MgSO.sub.4), filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel with 5%
methanol/dichloromethane to provide 30 mg of the desired product.
MS (ESI(+)) m/e 392 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.28 (s, 3H), 4.25 (s, 2H), 6.60 (d, J=5.76
Hz, 2H), 6.82 (m, J=5.09, 3.05 Hz, 1H), 7.11 (m, 2H), 7.33 (d,
J=8.48 Hz, 1H), 7.54 (d, J=8.81 Hz, 2H), 8.01 (dd, J=7.97, 2.20 Hz,
1H), 8.51 (d, J=2.71 Hz, 1H), 9.14 (s, 1H), 9.84 (s, 1H), 11.58 (s,
1H).
Example 121
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
Example 121A
4-(4-aminophenyl)-7-(methoxymethoxy)-1H-indazol-3-amine
The desired product was prepared by substituting Example 119A for
Example 15E in Examples 15F-G. MS (ESI(+)) m/e 285 (M+H).sup.+.
Example 121B
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-fluoropheny-
l)urea
The desired product was prepared by substituting Example 121A for
Example 15G in Example 15H.
Example 121C
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 121B for Example 119B in Example 120, then
purifying the resulting product by HPLC using the conditions
described in Example 15H. MS (ESI(+)) m/e 378 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 6.68-6.72 (m, 2H), 6.79 (td,
J=8.34, 2.34 Hz, 1H), 7.14 (d, J=8.11 Hz, 1H), 7.31 (m, 1H), 7.35
(d, J=8.42 Hz, 2H), 7.51 (dt, J=12.01, 2.26 Hz, 1H), 7.56 (d,
J=8.42 Hz, 2H), 8.88 (s, 1H), 8.97 (s, 1H).
Example 122
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
Example 122A
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-bromophenyl-
)urea
The desired product was prepared by substituting Example 121A and
1-bromo-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Example 122B
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 122A for Example 119B in Example 120 then
purifying the resulting product by HPLC using the conditions
described in Example 15H. MS (ESI(+)) m/e 438 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 6.69-6.73 (m, 2H), 7.16 (d,
J=7.80 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H), 7.32-7.34 (m, 1H), 7.35
(d, J=8.42 Hz, 2H), 7.56 (d, J=8.73 Hz, 2H), 7.88 (t, J=1.87 Hz,
1H), 8.90 (s, 1H), 8.95 (s, 1H).
Example 123
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
Example 123A
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-ethylphenyl-
)urea
The desired product was prepared by substituting Example 121A and
1-ethyl-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Example 123B
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 123A for Example 119B in Example 120 then
purifying the resulting product by HPLC using the conditions
described in Example 15H. MS (ESI(+)) m/e 388 (M+H).sup.+; NMR (500
MHz, DMSO-d.sub.6) .delta. 1.19 (t, J=7.49 Hz, 3H), 2.58 (q, J=7.49
Hz, 2H), 6.65-6.70 (m, 2H), 6.83 (d, J=7.49 Hz, 1H), 7.19 (t,
J=7.80 Hz, 1H), 7.27 (d, J=8.11 Hz, 1H), 7.33-7.34 (m, 3H), 7.55
(d, J=8.42 Hz, 2H), 8.64 (s, 1H), 8.74 (s, 1H).
Example 124
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluorom-
ethyl)phenyl]urea
Example 124A
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-[2-fluoro-5-(t-
rifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 121A and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Example 124B
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluorom-
ethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 124A for Example 119B in Example 120 then
purifying the resulting product by HPLC using the conditions
described in Example 15H. MS (ESI(+)) m/e 446 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 6.68-6.72 (m, 2H), 7.37 (d,
J=8.42 Hz, 2H), 7.38-7.40 (m, 1H), 7.51 (m, 1H), 7.57 (d, J=8.73
Hz, 2H), 8.64 (dd, J=7.17, 2.18 Hz, 1H), 8.93 (d, J=2.81 Hz, 1H),
9.28 (s, 1H).
Example 125
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluorom-
ethyl)phenyl]urea
Example 125A
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-[4-fluoro-3-(t-
rifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 121A and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Example 125B
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluorom-
ethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 125A for Example 119B in Example 120 then
purifying the resulting product by HPLC using the conditions
described in Example 15H. MS (ESI(-)) m/e 444 (M-H).sup.-; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 6.72-6.76 (m, 2H), 7.36 (d,
J=8.42 Hz, 2H), 7.44 (t, J=9.67 Hz, 1H), 7.58 (d, J=8.73 Hz, 2H),
7.65-7.68 (m, 1H), 8.03 (dd, J=6.39, 2.65 Hz, 1H), 9.02 (s, 1H),
9.19 (s, 1H).
Example 126
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
Example 126A
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chloropheny-
l)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 121A and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H.
Example 126B
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 126A for Example 119B in Example 120 then
purifying the resulting product by HPLC using the conditions
described in Example 15H. MS (ESI(-)) m/e 392 (M-H).sup.-; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 6.69-6.73 (m, 1H), 7.01-7.03
(m, 1H), 7.30-7.31 (m, 2H), 7.35 (d, J=8.73 Hz, 2H), 7.56 (d,
J=8.73 Hz, 2H), 7.74 (d, J=1.87 Hz, 1H), 8.91 (s, 1H), 8.98 (s,
1H).
Example 127
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phe-
nyl]urea
Example 127A
N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(trifluorom-
ethyl)phenyl]urea
The desired product was prepared by substituting Example 121A and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Example 127B
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phe-
nyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 127A for Example 119B in Example 120 then
purifying the resulting product by HPLC using the conditions
described in Example 15H. MS (ESI(+)) m/e 428 (M+H).sup.+; .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 6.70-6.74 (m, 2H), 7.32 (d,
J=7.49 Hz, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95 Hz, 1H),
7.58 (d, J=8.42 Hz, 2H), 7.60 (d, J=9.04 Hz, 1H), 8.04 (s, 1H),
8.96 (s, 1H), 9.14 (s, 1H).
Example 128
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-phenylurea
Example 128A
N-{-4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N'-phenylurea
The desired product was prepared by substituting Example 121A and
isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene,
respectively, in Example 15H.
Example 128B
N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N'-phenylurea
The desired product can be prepared by substituting Example 128A
for Example 119B in Example 120. MS (ESI(-)) m/e 358 (M-H).sup.-;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.57-6.64 (m, 2H), 6.97
(t, J=7.29 Hz, 1H), 7.29 (t, J=8.13 Hz, 2H), 7.32 (d, J=8.82 Hz,
2H), 7.47 (d, J=7.46 Hz, 2H), 7.54 (d, J=8.82 Hz, 2H), 8.71 (s,
1H), 8.77 (s, 1H).
Example 129
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phen-
ylurea
Example 129A
4-(4-aminophenyl)-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-3-amine
The desired product was prepared by substituting
2-(1-pyrrolidinyl)ethanol for 2-(4-morpholinyl)ethanol in Examples
75A and 75B. MS (ESI(+)) m/e 338 (M+H).sup.+.
Example 129B
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phen-
ylurea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 129A and isocyanatobenzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 457 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.93 (br s, 2H), 2.08 (br s, 2H), 3.25 (br s, 4H), 3.68 (br
s, 2H), 4.46 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d,
J=7.80 Hz, 1H), 6.98 (t, J=7.33 Hz, 1H), 7.29 (t, J=7.80 Hz, 2H),
7.36 (d, J=8.73 Hz, 2H), 7.47 (d, J=7.49 Hz, 2H), 7.58 (d, J=8.42
Hz, 2H), 8.74 (s, 1H), 8.82 (s, 1H).
Example 130
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-f-
luorophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 129A for Example 15G in Example 15H. MS
(ESI(+)) m/e 475 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.92 (br s, 2H), 2.07 (br s, 2H), 3.24 (br s, 2H), 3.68 (br
s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.49 Hz, 1H), 6.79 (td,
J=8.50, 2.34 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (dd, J=8.11,
1.25 Hz, 1H), 7.29-7.34 (m, 1H), 7.37 (d, J=8.73 Hz, 2H), 7.52 (dt,
J=12.01, 2.26 Hz, 1H), 7.58 (d, J=8.73 Hz, 2H), 9.00 (s, 1H), 9.08
(s, 1H).
Example 131
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)
-N'-(2-fluoro-5-methylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 129A and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 489 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.93 (br s, 2H), 2.07 (br s, 2H), 2.28 (s, 3H), 3.25 (br s,
2H), 3.69 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz,
1H), 6.80-6.82 (m, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.11 (dd, J=11.38,
8.26 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.73 Hz, 2H),
7.99 (dd, J=7.80, 1.56 Hz, 1H), 8.53 (d, J=2.49 Hz, 1H), 9.20 (s,
1H).
Example 132
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-m-
ethylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 129A and 1-isocyanato-3-methylbenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 471 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.93 (br s, 2H), 2.07 (br s, 2H), 2.29 (s,
3H), 3.25 (br s, 2H), 169 (br s, 4H), 4.48 (t, J=4.80 Hz, 2H), 6.77
(d, J=7.80 Hz, 1H), 6.80 (d, J=7.49 Hz, 1H), 6.90 (d, J=7.80 Hz,
1H), 7.16 (t, J=7.80 Hz, 1H), 7.26 (d, J=8.11 Hz, 1H), 7.33 (s,
1H), 7.36 (d, J=8.73 Hz, 2H), 7.59 (d, J=8.73 Hz, 2H), 8.79 (s,
1H), 8.95 (s, 1H).
Example 133
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-b-
romophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 129A and 1-bromo-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 535 and 537 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 1.93 (br s, 2H), 2.07 (br s, 2H),
3.25 (br s, 2H), 3.68 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.75 (d,
J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (d, J=8.11 Hz, 1H),
7.25 (t, J=8.11 Hz, 1H), 7.34 (d, J=9.36 Hz, 1H), 7.37 (d, J=8.42
Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 7.89 (t, J=1.87 Hz, 1H), 9.06 (s,
1H), 9.10 (s, 1H).
Example 134
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[2-f-
luoro-5-(trifluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 129A and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 543 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.93 (br s, 2H), 2.08 (br s, 2H), 3.25 (br s, 2H), 3.69 (br
s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d,
J=7.80 Hz, 1H), 7.39 (d, J=8.42 Hz, 2H), 7.41 (m, 1H), 7.51 (t,
J=9.67 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 8.64 (dd, J=7.33, 2.34 Hz,
1H), 8.94 (d, J=2.49 Hz, 1H), 9.30 (s, 1H).
Example 135
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-c-
hlorophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 129A and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 491 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.93 (br s, 2H), 2.07 (br s, 2H), 3.25 (br s,
2H), 3.68 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.76 (d, J=7.49 Hz,
1H), 6.90 (d, J=7.80 Hz, 1H), 7.02 (m, 1H), 7.31 (d, J=5.30 Hz,
2H), 7.37 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.73 Hz, 2H), 7.74 (s,
1H), 9.10 (s, 1H), 9.15 (s, 1H).
Example 136
N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(-
trifluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 129A and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 525 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.93 (br s, 2H), 2.07 (br s, 2H), 3.25 (br s, 2H), 3.68 (br
s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d,
J=7.80 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H),
7.52 (t, J=7.80 Hz, 1H), 7.60 (d, J=8.42 Hz, 2H), 7.60 (d, J=6.55
Hz, 1H), 8.05 (s, 1H), 9.10 (s, 1H), 9.28 (s, 1H).
Example 137
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phenyl-
urea
Example 137A
4-(4-aminophenyl)-7-[2-(diethylamino)ethoxy]-1H-indazol-3-amine
The desired product was prepared by substituting
2-(diethylamino)ethanol for 2-(4-morpholinyl)ethanol in Examples
75A and 75B. MS (ESI(+)) m/e 340 (M+H).sup.+.
Example 137B
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-phenyl-
urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 137A and isocyanatobenzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 459 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.27 (t, J=7.17 Hz, 6H), 3.33 (br s, 4H), 3.62 (br s, 2H),
4.49 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.80
Hz, 1H), 6.98 (t, J=7.49 Hz, 1H), 7.29 (t, J=7.95 Hz, 2H), 7.36 (d,
J=8.42 Hz, 2H), 7.48 (d, J=7.80 Hz, 2H), 7.58 (d, J=8.73 Hz, 2H),
8.83 (s, 1H), 8.91 (s, 1H).
Example 138
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-flu-
orophenyl)urea
The desired product was prepared as the bis(trifluoroacetate salt)
by substituting Example 137A for Example 15G in Example 15H. MS
(ESI(+)) m/e 477 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.27 (t, J=7.33 Hz, 6H), 3.34 (br s, 4H), 3.60 (br s, 2H),
4.49 (t, J=4.80 Hz, 2H), 6.76 (d, J=7.80 Hz, 1H), 6.79 (t, J=8.58
Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (d, J=8.11 Hz, 1H), 7.31 (q,
J=7.61 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.52 (dt, J=11.93, 2.14
Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 9.02 (s, 1H), 9.11 (s, 1H).
Example 139
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(2-flu-
oro-5-methylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate salt)
by substituting Example 137A and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 491 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.27 (t, J=7.33 Hz, 6H), 2.28 (s, 3H), 3.33 (br d, J=8.42
Hz, 4H), 3.62 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80
Hz, 1H), 6.80-6.82 (m, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.11 (dd,
J=11.38, 8.26 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz,
2H), 7.99 (dd, J=7.95, 1.72 Hz, 1H), 8.54 (d, J=2.50 Hz, 1H), 9.22
(s, 1H).
Example 140
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-met-
hylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate salt)
by substituting Example 137A and 1-isocyanato-3-methylbenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 473 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.27 (t, J=7.33 Hz, 6H), 2.29 (s, 3H), 3.34
(br s, 4H), 3.61 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.74 (d,
J=7.49 Hz, 1H), 6.80 (d, J=7.17 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H),
7.16 (t, J=7.80 Hz, 1H), 7.26 (d, J=8.11 Hz, 1H), 7.32 (s, 1H),
7.35 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 8.72 (s, 1H),
8.87 (s, 1H).
Example 141
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-bro-
mophenyl)urea
The desired product was prepared as the bis(trifluoroacetate salt)
by substituting Example 137A and 1-bromo-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 537 and 539 (M+H).sup.+; .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 1.27 (t, J=7.33 Hz, 6H), 3.30-3.35
(m, 4H), 3.61 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80
Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.16 (d, J=7.80 Hz, 1H), 7.25 (t,
J=7.95 Hz, 1H), 7.33-7.35 (m, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.59
(d, J=8.42 Hz, 2H), 7.89 (m, 1H), 9.05 (s, 1H), 9.09 (s, 1H).
Example 142
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[2-flu-
oro-5-(trifluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 137A and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 545 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.27 (t, J=7.17 Hz, 6H), 3.33 (br s, 4H), 3.62 (br s, 2H),
4.50 (t, J=4.80 Hz, 2H), 6.77 (d, J=7.80 Hz, 1H), 6.89 (d, J=7.80
Hz, 1H), 7.39 (m, J=8.42 Hz, 3H), 7.51 (t, J=9.85 Hz 1H), 7.60 (d,
J=8.73 Hz, 2H), 8.64 (dd, J=7.17, 2.18 Hz, 1H), 8.97 (d, J=2.81 Hz,
1H), 9.35 (s, 1H).
Example 143
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-(3-chl-
orophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 137A and 1-chloro-3-isocyanatobenzene for
Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 493 (M+H).sup.+; .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 1.27 (t, J=7.17 Hz, 6H), 3.34 (br s, 4H),
3.62 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H),
6.88 (d, J=7.80 Hz, 1H), 7.02 (td, J=4.37, 2.18 Hz, 1H), 7.30-7.31
(m, 2H), 7.37 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 7.74 (s,
1H), 9.01 (s, 1H), 9.06 (s, 1H).
Example 144
N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(tr-
ifluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 137A and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+)) m/e 527 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 1.27 (t, J=7.33 Hz, 6H), 3.32-3.34 (br s, 4H), 3.61 (br s,
2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.88 (d,
J=7.49 Hz, 1H), 7.31 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H),
7.52 (t, J=7.95 Hz, 1H), 7.60-7.61 (m, 3H), 8.05 (s, 1H), 9.12 (s,
1H), 9.30 (s, 1H).
Example 145
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H--
indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
Example 145A
3-(2-{[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]oxy}ethyl)-1,5,5-trimethy-
l-2,4-imidazolidinedione
The desired product was prepared by substituting
3-(2-hydroxyethyl)-1,5,5-trimethyl-2,4-imidazolidinedione for
2-(4-morpholinyl)ethanol in Examples 75A and 75B. NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.27 (s, 6H), 2.80 (s, 3H), 3.81 (t, J=6.27
Hz, 2H), 4.32 (t, J=6.27 Hz, 2H), 5.19 (s, 2H), 6.57 (d, J=7.80 Hz,
1H), 6.65 (d, J=8.14 Hz, 2H), 6.76 (d, J=7.80 Hz, 1H), 7.07 (d,
J=8.14 Hz, 2H), 11.59 (s, 1H); MS (ESI(+)) m/e 409 (M+H).sup.+.
Example 145B
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H--
indazol-4-yl}phenyl)-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 145A and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 1.27 (s, 6H), 2.29 (s, 3H), 2.81 (s,
3H), 3.83 (t, J=5.93 Hz, 2H), 4.35 (t, J=5.93 Hz, 2H), 6.68 (d,
J=7.80 Hz, 1H), 6.81 (t, J=7.46 Hz, 2H), 7.05-7.45 (m, 5H), 7.56
(d, J=8.48 Hz, 2H), 8.62 (s, 1H), 8.75 (s, 1H), 11.75 (s, 1H); MS
(ESI(+)) m/e 542 (M+H).sup.+.
Example 146
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H--
indazol-4-yl}phenyl)-N'-(3-chlorophenyl)urea
The desired product was prepared by substituting Example 145A and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.27 (s, 6H), 2.81 (s, 3H), 3.83
(t, J=6.27 Hz, 2H), 4.35 (t, J=6.44 Hz, 2H), 6.68 (d, J=7.80 Hz,
1H), 6.82 (d, J=7.80 Hz, 1H), 6.95-7.06 (m, 1H), 7.25-7.40 (m, 4H),
7.56 (d, J=8.81 Hz, 2H), 7.73 (s, 1H), 8.86 (s, 1H), 8.93 (s, 1H),
11.74 (s, 1H); MS (ESI(+)) m/e 562 (M+H).sup.+.
Example 147
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H--
indazol-4-yl}phenyl)-N'-(2-fluoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 145A and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H then
purifying the resulting product by flash column chromatography on
silica gel with 5-8% methanol/dichloromethane. NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.27 (s, 6H), 2.28 (s, 3H), 2.81 (s, 3H),
3.83 (t, J=6.27 Hz, 2H), 4.35 (t, J=6.27 Hz, 2H), 6.67 (d, J=7.80
Hz, 1H), 6.70-6.90 (m, 2H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.36
(d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 7.90-8.10 (dd, J=7.97,
1.86 Hz, 1H), 8.52 (d, J=2.71 Hz, 1H), 9.17 (s, 1H), 11.72 (s, 1H);
MS (ESI(+)) m/e 560 (M+H).sup.+.
Example 148
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H--
indazol-4-yl}phenyl)-N'-[3-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 145A and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.27 (s, 6H), 2.81 (s, 3H),
3.83 (t, J=6.27 Hz, 2H), 4.35 (t, J=6.44 Hz, 2H), 6.68 (d, J=7.80
Hz, 1H), 6.82 (d, J=8.14 Hz, 1H), 7.25-7.45 (m, 3H), 7.45-7.65 (m,
4H), 8.04 (s, 1H), 8.90 (s, 1H), 9.09 (s, 1H), 11.73 (s, 1H); MS
(ESI(+)) m/e 596 (M+H).sup.+.
Example 149
N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N'-(2-fluoro-5-methylphenyl)-
urea
Example 149A
N-(4-bromo-2-ethylphenyl)-N'-(2-fluoro-5-methylphenyl)urea
A solution of 4-bromo-2-ethylaniline (200 mg) in dichloromethane
(10 mL) was treated with 1-fluoro-2-isocyanato-4-methylbenzene (151
mg), stirred at room temperature overnight, diluted with hexanes,
and filtered. The filter cake provided 227 mg of the desired
product. MS (ESI(+)) m/e 351,353 (M+H).sup.+.
Example 149B
N-[2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-(2-fl-
uoro-5-methylphenyl)urea
A mixture of Example 149A (219 mg, 0.62 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (190 mg,
0.75 mmol), potassium acetate (183 mg), and
PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (15 mg) in DMF (6 mL) was
degassed then heated to 80.degree. C. for 2 hours. The mixture was
used directly in the next reaction.
Example 149C
N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N'-(2-fluoro-5-methylphenyl)-
urea
The desired product was prepared by substituting Example 149B and
PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 for Example 1B and
Pd(PPh.sub.3).sub.4, respectively, in Example 1C. Additionally, DMF
was used in place of DME. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 1.24 (t, J=7.46 Hz, 3H), 2.28 (s, 3H), 2.71 (q, J=7.46 Hz,
2H), 4.35 (s, 2H), 6.75-6.85 (m, 2H), 7.12 (dd, J=11.53, 8.14 Hz,
1H), 7.25-7.35 (m, 4H), 7.99 (d, J=8.14 Hz, 1H), 8.06 (dd, J=7.80,
2.03 Hz, 1H), 8.44 (s, 1H), 8.99 (d, J=2.03 Hz, 1H), 11.71 (s, 1H);
MS (ESI(+)) m/e 404 (M+H).sup.+.
Example 150
N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N'-[3-(trifluoromethyl)pheny-
l]urea
The desired product was prepared by substituting
1-isocyanato-3-(trifluoromethyl)benzene for
1-fluoro-2-isocyanato-4-methylbenzene in Examples 149A-C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.24 (t, J=7.46 Hz, 3H), 2.71
(q, J=7.69 Hz, 2H), 4.35 (s, 2H), 6.75-6.90 (m, 1H), 7.20-7.40 (m,
4H), 7.45-7.60 (m, 3H), 7.94 (d, J=8.14 Hz, 1H), 8.07 (s, 1H), 8.13
(s, 1H), 9.43 (s, 1H), 11.72 (s, 1H); MS (ESI(+)) m/e 440
(M+H).sup.+.
Example 151
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 26B and 1-fluoro-2-isocyanato-4-methylbenzene
for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.27 (s,
3H), 6.74-6.83 (m, 2H), 7.13 (m, 2H), 7.38 (d, J=8.29 Hz, 2H), 7.58
(d, J=8.59 Hz, 2H), 7.99 (d, J=6.44 Hz, 1H), 8.52 (d, J=2.45 Hz,
1H), 9.21 (s, 1H); MS (ESI(+)) m/e 394 (M+H).sup.+.
Example 152
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(2-flu-
oro-5-methylphenyl)urea
Example 152A
2,3-difluoro-4-(hydroxymethyl)-6-iodobenzonitrile
A -78.degree. C. solution of Example 26A (5.0 g, 18.9 mmol) in THF
was treated with LDA (2M in hexanes, 11.5 mL, 22.6 mmol), stirred
for 1 hour at -78.degree. C., treated with methyl formate (2.34 mL,
37.8 mmol), stirred at -78.degree. C. for 30 minutes, warmed to
0.degree. C. for 1 hour, quenched with saturated NH.sub.4Cl and
extracted three times with ethyl acetate. The combined extracts
were washed with brine, dried (MgSO.sub.4), filtered, and
concentrated. The residue was immediately dissolved in ethanol (100
mL), cooled to 0.degree. C., and treated portionwise with
NaBH.sub.4 (1.08 g). The reaction was stirred at 0.degree. C. for 2
hours, quenched with acetone, stirred for 5 minutes, poured into
water, and extracted three times with ethyl acetate. The combined
extracts were washed with brine, dried (MgSO.sub.4), filtered, and
concentrated. The residue was purified by flash column
chromatography on silica gel with 2:1 hexanes/ethyl acetate to give
1.02 g of the desired product. R.sub.f=0.84 (ethyl acetate).
Example 152B
(3-amino-7-fluoro-4-iodo-1H-indazol-6-yl)methanol
The desired product was prepared by substituting Example 152A for
2-fluoro-6-iodobenzonitrile in Example 1A. R.sub.f=0.53 (ethyl
acetate).
Example 152C
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(2-flu-
oro-5-methylphenyl)urea
A mixture of Example 152B (50 mg, 0.16 mmol), Example 5A (66 mg,
0.18 mmol), Pd(PPh.sub.3).sub.4 (9 mg, 0.008 mmol), and
Na.sub.2CO.sub.3 (43 mg, 0.4 mmol) in toluene (2 mL), ethanol (1
mL), and water (1 mL) was degassed and heated at 140.degree. C. for
8 minutes with stirring using a Smith Synthesizer in a septa capped
5 mL process vial at 300 W. The samples were cooled using 40 psi
pressurized air. The mixture was concentrated and the residue was
purified by preparative HPLC on a Waters Symmetry C8 column (25
mm.times.100 mm, 7 .mu.m particle size) using a gradient of 10% to
100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run
time) at a flow rate of 40 mL/min to provide 26 mg of the desired
product as the trifluoroacetate salt. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.28 (s, 3H), 4.65 (d, J=1.36 Hz, 2H), 6.81
(m, 1H), 6.86 (d, J=5.76 Hz, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H),
7.39 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80,
2.03 Hz, 1H), 8.53 (d, J=2.37 Hz, 1H), 9.21 (s, 1H); MS (ESI(+))
m/e 424 (M+H).sup.+.
Example 153
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-[3-(tr-
ifluoromethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 98A for Example 5A in Example 152C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 4.65 (d, J=1.70 Hz, 2H), 6.87
(d, J=5.76 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d, J=8.48 Hz,
2H), 7.53 (t, J=7.97 Hz, 1H), 7.58-7.64 (m, 3H), 8.04 (s, 1H), 8.99
(s, 1H), 9.14 (s, 1H); MS (ESI(+)) m/e 460 (M+H).sup.+; Anal.
calcd. for
C.sub.22H.sub.17F.sub.4N.sub.5O.sub.2.1.0CF.sub.3CO.sub.2H: C,
50.27; H, 3.15; N, 12.21. Found: C, 50.15; H, 3.15; N, 12.41.
Example 154
N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(3-chl-
orophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting
N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]urea for Example 5A in Example 152C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 4.65 (d, J=1.36 Hz, 2H), 6.86 (d, J=5.76 Hz,
1H), 7.03 (td, J=4.41, 2.03 Hz, 1H), 7.27-7.36 (m, 2H), 7.39 (d,
J=8.48 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H), 7.74 (m, 1H), 8.93 (s,
1H), 8.96 (s, 1H); MS (ESI(+)) m/e 426 (m+H).sup.+.
Example 155
N-{-4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(3-me-
thylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 1B for Example 5A in Example 152C. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 4.65 (d, J=1.36 Hz,
2H), 6.80 (d, J=7.46 Hz, 1H), 6.84 (d, J=5.76 Hz, 1H), 7.17 (t,
J=7.80 Hz, 1H), 7.25 (d, J=7.80 Hz, 1H), 7.32 (s, 1H), 7.37 (d,
J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.64 (s, 1H), 8.80 (s,
1H); MS (ESI(+)) m/e 406 (M+H).sup.+.
Example 156
N-{-4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N'-(3-fl-
uorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting
N-(3-fluorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]urea for Example 5A in Example 152C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 4.65 (d, J=1.02 Hz, 2H), 6.80 (td, J=8.65,
2.71 Hz, 1H), 6.84 (d, J=5.76 Hz, 1H), 7.14 (d, J=9.16 Hz, 1H),
7.32 (m, 1H), 7.38 (d, J=8.48 Hz, 2H), 7.51 (dt, J=11.87, 2.20 Hz,
1H), 7.59 (d, J=8.48 Hz, 2H), 12.13 (s, 1H); MS (ESI(+)) m/e 410
(M+H).sup.+.
Example 157
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N'-
-(2-fluoro-5-methylphenyl)urea
Example 157A
4-[(diethylamino)methyl]-2,3-difluoro-6-iodobenzonitrile
A 0.degree. C. solution of Example 152A (350 mg, 1.18 mmol) in
dichloromethane (10 mL) was treated with triethylamine (0.25 mL,
1.78 mmol) and methanesulfonyl chloride (0.1 mL, 1.3 mmol), stirred
at 0.degree. C. for 1 hour, treated with diethylamine (0.245 mL,
2.37 mmol), and overnight at room temperature. The mixture was
partitioned between 1N NaOH and dichloromethane and the organic
extract was dried (MgSO.sub.4), filtered, and concentrated. The
residue was purified by flash column chromatography on silica gel
with 3:1 hexanes/ethyl acetate to provide 0.263 g of the desired
product. MS (ESI(+)) 351 (M+H).sup.+.
Example 157B
6-[(diethylamino)methyl]-7-fluoro-4-iodo-1H-indazol-3-amine
The desired product was prepared by substituting Example 157A for
2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) 363
(M+H).sup.+.
Example 157C
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N'-
-(2-fluoro-5-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 157B for Example 152B in Example 152C. .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 1.27 (t, J=7.29 Hz, 6H), 2.28
(s, 3H), 3.18 (m, 4H), 4.48 (d, J=4.75 Hz, 2H), 6.82 (ddd, J=7.71,
5.17, 2.03 Hz, 1H), 6.94 (d, J=5.76 Hz, 1H), 7.12 (dd, J=11.36,
8.31 Hz, 1H), 7.44 (d, J=8.48 Hz, 2H), 7.63 (d, J=8.82 Hz, 2H),
7.99 (dd, J=7.97, 1.87 Hz, 1H), 8.56 (d, J=2.71 Hz, 1H), 9.27 (s,
1H), 9.36 (br s, 1H); MS (ESI(+) 477 (M+H).sup.+.
Example 158
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N'-
-[3-(trifluoromethyl)phenyl]urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 157B and Example 98A for Example 152B and
Example 5A, respectively, in Example 152C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.27 (t, J=7.29 Hz, 6H), 3.18 (m, 4H), 4.48
(d, J=4.75 Hz, 2H), 6.94 (d, J=5.76 Hz, 1H), 7.33 (d, J=7.80 Hz,
1H), 7.44 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.80 Hz, 1H), 7.60 (m,
1H), 7.65 (d, J=8.48 Hz, 2H), 8.06 (s, 1H), 9.14 (s, 1H), 9.27 (s,
1H), 9.34 (br s, 1H); MS (ESI(+)) m/e 515 (M+H).sup.+.
Example 159
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N--
(3-chlorophenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 157B and
N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]urea for Example 152B and Example 5A, respectively, in Example
152C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.27 (t, J=7.29
Hz, 6H), 3.19 (m, 4H), 4.48 (d, J=4.75 Hz, 2H), 6.94 (d, J=5.76 Hz,
1H), 7.03 (dt, J=6.44, 2.20 Hz, 1H), 7.27-7.37 (m, 2H), 7.44 (d,
J=8.82 Hz, 2H), 7.63 (d, J=8.48 Hz, 2H), 7.75 (m, 1H), 9.06 (s,
1H), 9.32 (br s, 1H); MS (ESI(+)) m/e 481 (M+H).sup.+.
Example 160
N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N'-
-(3-methylphenyl)urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 157B and Example 1B for Example 152B and
Example 5A, respectively, in Example 152C. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.27 (t, J=7.12 Hz, 6H), 2.29 (s, 3H), 3.18
(m, 4H), 4.48 (d, J=4.75 Hz, 2H), 6.81 (d, J=7.12 Hz, 1H), 6.94 (d,
J=5.76 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.26 (m, 1H), 7.32 (s,
1H), 7.42 (d, J=8.48 Hz, 2H), 7.63 (d, J=8.48 Hz, 2H), 8.74 (s,
1H), 8.93 (s, 1H), 9.34 (br s, 1H); MS (ESI(+)) m/e 461
(M+H).sup.+.
Example 161
N-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(tr-
ifluoromethyl)phenyl]urea
Example 161A
4-iodo-7-[(3-pyridinyloxy)methyl]-1H-indazol-3-amine
The desired product was prepared by substituting 3-pyridinol for
morpholine in Examples 15E-F.
Example 161B
N-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1H-indazol-4-yl}phenyl)-N-[3-(tri-
fluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 161A and
Example 98A for Example 152B and Example 5A, respectively, in
Example 152C then purifying the resulting product by flash column
chromatography on silica gel with 5-8% methanol/dichloromethane.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 4.38 (s, 2H), 5.40 (s,
2H), 7.32 (d, J=7.17 Hz, 1H), 7.34-7.38 (m, 2H), 7.42 (d, J=8.42
Hz, 2H), 7.52 (dd, J=15.59, 7.80 Hz, 2H), 7.58-7.64 (m, 4H), 8.04
(s, 1H), 8.19 (d, J=4.68 Hz, 1H), 8.39 (d, J=2.50 Hz, 1H), 8.96 (s,
1H), 9.12 (s, 1H), 11.92 (s, 1H); MS (ESI(+)) m/e 519
(M+H).sup.+.
Example 162
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(2-flu-
oro-5-methylphenyl)urea
Example 162A
2-(4-iodo-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione
A mixture of Example 1A (1.09 g) and phthalic anhydride (0.75 g) in
dioxane (15 mL) was stirred overnight at 120.degree. C. and
concentrated. The residue was triturated from diethyl ether (15 mL)
to provide 0.51 g of the desired product. MS (ESI(+)) m/e 388
(M+H).sup.+.
Example 162B
2-{4-iodo-1-[2-(4-morpholinyl)ethyl]-1H-indazol-3-yl}-1H-isoindole-1,3(2H)-
-dione
A mixture of Example 162A (100 mg), 4-(2-chloroethyl)morpholine (48
mg), and Na.sub.2CO.sub.3 (82 mg) in DMF (5 mL) was heated
overnight at 80.degree. C., cooled to room temperature, and
partitioned between 1N HCl and ethyl acetate. The aqueous layer was
basified with 1N KOH and extracted with ethyl acetate. The extract
was dried (MgSO.sub.4), filtered, and concentrated to provide 45 mg
of the desired product. MS (ESI(+)) m/e 503 (M+H).sup.+.
Example 162C
4-iodo-1-[2-(4-morpholinyl)ethyl]-1H-indazol-3-amine
A mixture of hydrazine hydrate (0.058 mL) and Example 162B (120 mg,
0.24 mmol) in ethanol (5 mL) was stirred at 0.degree. C. for 3
hours and concentrated. The residue was purified by flash column
chromatography on silica gel with 5-8% methanol/dichloromethane to
provide 95 mg of the desired product.
Example 162D
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(2-flu-
oro-5-methylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 162C for Example 152B in Example 152C. MS
(ESI(+)) m/e 489 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
E, 2.28 (s, 3H), 2.45 (d, J=4.07 Hz, 4H), 2.68 (t, J=6.61 Hz, 2H),
3.54 (t, J=4.05 Hz, 4H), 4.26 (t, J=6.44 Hz, 2H), 4.41 (s, 2H),
6.78-6.83 (d, J=6.78 Hz, 2H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.31
(t, J=8.48 Hz, 1H), 7.36-7.41 (m, 3H), 7.59 (d, J=8.48 Hz, 2H),
8.01 (d, J=7.46 Hz, 1H), 8.54 (s, 1H), 9.21 (s, 1H).
Example 163
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-flu-
orophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting 162C for Example 15F in Examples 15G-H. MS (ESI(+))
m/e 475 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
3.58 (t, J=5.77 Hz, 2H), 3.32-3.83 (br m, 8H), 4.55 (t, J=6.24 Hz,
2H), 6.79 (td, J=8.42, 1.87 Hz, 1H), 6.88 (d, J=6.55 Hz, 1H), 7.15
(dd, J=8.26, 1.09 Hz, 1H), 7.29-7.34 (m, 1H), 7.38-7.42 (m, J=8.11,
8.11 Hz, 3H), 7.48 (d, J=8.11 Hz, 1H), 7.52 (dt, J=11.85, 2.18 Hz,
1H), 7.62 (d, J=8.73 Hz, 2H), 9.06 (s, 1H), 9.12 (s, 1H).
Example 164
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-chl-
orophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 162C and 1-chloro-3-isocyanatobenzene for
Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in
Examples 15G-H. MS (ESI(+)) m/e 491 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 3.58 (t, J=5.92 Hz, 2H), 3.38-3.92 (br
m, 8H), 4.55 (t, J=6.39 Hz, 2H), 6.88 (d, J=6.86 Hz, 1H), 7.02-7.04
(m, 1H), 7.31-7.32 (m, 2H), 7.38-7.41 (m, J=7.95, 7.95 Hz, 3H),
7.48 (d, J=8.11 Hz, 1H), 7.62 (d, J=8.73 Hz, 2H), 7.74 (s, 1H),
9.09 (s, 1H), 9.11 (s, 1H).
Example 165
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N-[3-(tri-
fluoromethyl)phenyl]urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 162C and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15F and
1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H. MS
(ESI(+)) m/e 525 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 3.32-3.83 (br m, 8H), 3.58 (t, J=5.77 Hz, 2H), 4.55 (t,
J=6.39 Hz, 2H), 6.88 (d, J=7.17 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H),
7.39-7.42 (m, 3H), 7.48 (d, J=8.42 Hz, 1H), 7.53 (t, J=7.95 Hz,
1H), 7.61 (d, J=8.73 Hz, 1H), 7.64 (d, J=8.73 Hz, 2H), 8.05 (s,
1H), 9.15 (s, 1H), 9.29 (s, 1H).
Example 166
N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-met-
hylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 162C and 1-isocyanato-3-methylbenzene for
Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in
Examples 15G-H. MS (ESI(+)) m/e 471 (M+H).sup.+; .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 2.29 (s, 3H), 3.58 (t, J=5.77 Hz, 2H),
3.39-3.88 (br m, 8H), 4.55 (t, J=6.39 Hz, 2H), 6.80 (d, J=7.49 Hz,
1H), 6.87 (d, J=6.86 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.26 (d,
J=8.42 Hz, 1H), 7.32 (s, 1H), 7.37-7.41 (m, 3H), 7.48 (d, J=8.11
Hz, 1H), 7.61 (d, J=8.42 Hz, 2H), 8.75 (s, 1H), 8.93 (s, 1H).
Example 167-I and 167-II
N-[4-(3-amino-6-bromo-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
and
N-[4-(3-amino-4-bromo-1H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea
Example 167A
2,4-dibromo-6-fluorobenzonitrile
The desired product was prepared by substituting
2,4-dibromo-6-fluorobenzoic acid (prepared as described in
Tetrahedron Lett. 1996, 37, 6551-6554) for Example 15A in Examples
15B and 15C.
Example 167B
4,6-dibromo-1H-indazol-3-amine
The desired product was prepared by substituting Example 167A for
2-fluoro-6-iodobenzonitrile in Example 1A. .sup.1H NMR
(DMSO-d.sub.6) .delta. 11.99 (111, br s), 7.48 (1H, d, J=1.6 Hz),
7.24 (1H, s), 5.22 (1H, d, J=8.0 Hz).
Example 167-I and 167II
N-[4-(3-amino-6-bromo-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
and
N-[4-(3-amino-4-bromo-1H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea
A mixture of Example 167B (0.060 g, 0.021 mmol), Example 1B (0.073
g, 0.21 mmol), Na.sub.2CO.sub.3 (0.052 g, 0.49 mmol), and
Pd(PPh.sub.3).sub.4 (0.014 g, 0.012 mmol) in 2:1 DME/water (1.2 mL)
was heated to 85.degree. C. in a sealed tube overnight. The
reaction was treated with additional Pd(PPh.sub.3).sub.4 (0.028 g,
0.024 mmol), heated for two days, treated with additional catalyst
(0.028 g, 0.024 mmol), heated to 160.degree. C. for 2 hours, and
cooled to room temperature. The mixture was diluted with ethyl
acetate and dichloromethane, filtered, and concentrated. The
concentrate was purified by flash column chromatography on silica
gel with methanol/dichloromethane (2:100 to 5:100), then purified
by preparative HPLC with 30-100% CH.sub.3CN/5 mM ammonium acetate
buffer over 9 minutes to provide the desired products.
Example 167-I
LC/MS 434.2 (M-H).sup.-, LC retention time 3.00 mM. .sup.1H NMR
(DMSO-d.sub.6) .delta. 7.508 (2H, d, J=8.4 Hz), 7.454 (1H, d, J=1.2
Hz), 7.407 (2H, d, J=8.4 Hz), 7.325 (1H, s), 7.257 (1H, d, J=6.0
Hz), 7.166 (1H, m), 6.888 (1H, s), 6.799 (1H, d, J=7.6 Hz), 4.397
(2H, s), 2.328 (3H, s).
Example 167-II
LC/MS 434.0 (M-H).sup.-, LC retention time 2.87 mM. .sup.1H NMR
(DMSO-d.sub.6) .delta. 11.88 (1H, br s), 8.961 (1H, br s), 8.782
(1H, br s), 7.637 (2H, d, J=8.8 Hz), 7.560 (1H, d, J=8.8 Hz), 7.414
(2H, d, J=1.2 Hz), 7.352 (1H, d, J=1.2 Hz), 7.319 (1H, s), 7.252
(1H, d, J=7.6 Hz), 7.181-7.142 (1H, m), 6.796 (1H, d, J=7.6 Hz),
5.147 (2H, d, J=9.2 Hz), 2.285 (3H, s).
Example 168
N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N'-(2-flu-
oro-5-methylphenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting N-(2-chloroethyl)-N,N-dimethylamine for
4-(2-chloroethyl)morpholine in Example 162. MS (ESI(+)) m/e 447
(M+H).sup.+; NMR (300 MHz, DMSO-d.sub.6) .delta. 2.28 (s, 3H), 2.87
(s, 3H), 2.88 (s, 3H), 3.54 (q, J=5.65 Hz, 2H), 4.52 (t, J=6.10 Hz,
2H), 6.79-6.84 (m, 1H), 6.88 (d, J=6.10 Hz, 1H), 7.12 (dd, J=11.36,
8.31 Hz, 1H), 7.37-7.42 (m, 3H), 7.50 (d, J=7.79 Hz, 2H), 7.61 (d,
J=8.48 Hz, 2H), 7.99 (dd, J=8.14, 2.03 Hz, 1H), 8.55 (d, J=2.37 Hz,
1H), 9.24 (s, 1H).
Example 169
N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-chl-
orophenyl)urea
Example 169A
1-[2-(dimethylamino)ethyl]-4-iodo-1H-indazol-3-amine
The desired product was prepared by substituting
N-(2-chloroethyl)-N,N-dimethylamine for 4-(2-chloroethyl)morpholine
in Example 162A-C.
Example 169B
N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N'-(3-chl-
orophenyl)urea
The desired product was prepared as the bis(trifluoroacetate) salt
by substituting Example 169A and
N-(3-chlorophenyl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl]urea for Example 152B (50 mg, 0.16 mmol) and Example 5A,
respectively, in Example 152C. MS (ESI(+)) m/e 449 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.87 (s, 3H) 2.88 (s,
3H) 3.55 (q, J=5.65 Hz, 2H) 4.52 (t, J=6.27 Hz, 2H) 6.87 (dd,
J=6.95, 0.85 Hz, 1H) 7.01-7.05 (m, 1H) 7.30-7.32 (m, 2H) 7.38-7.42
(m, 3H) 7.50 (d, J=8.48 Hz, 1H) 7.61 (d, J=8.48 Hz, 2H) 7.73-7.75
(m, 1H) 9.01 (s, 1H) 9.04 (s, 1H).
Example 170
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)pheny-
l]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide
Example 170A
tert-butyl 2-(3-cyano-2-fluoro-4-iodophenoxy)ethylcarbamate
The desired product was prepared by substituting tert-butyl
2-hydroxyethylcarbamate for 2-(4-morpholinyl)ethanol in Example
75A. R.sub.f=0.8 (1:1 ethyl acetate/hexanes).
Example 170B
N-[2-(3-cyano-2-fluoro-4-iodophenoxy)ethyl]methanesulfonamide
A mixture of Example 170A (317 mg, 0.78 mmol) in TFA (1 mL) and
CH.sub.2Cl.sub.2 (1 mL) was stirred at room temperature for 10
minutes and concentrated. The residue was partitioned between
saturated NaHCO.sub.3 and dichloromethane. The aqueous phase was
extracted twice with dichloromethane and the combined organic
extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated.
The concentrate was dissolved in pyridine (5 mL), treated with
methanesulfonyl chloride (0.07 mL), stirred at room temperature for
6 hours, concentrated, and partitioned between ethyl acetate and 1N
HCl. The organic extract was dried (Na.sub.2SO.sub.4), filtered,
and concentrated to provide the desired product. MS (ESI) m/e 383
(M-H).sup.-.
Example 170C
N-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide
The desired product was prepared by substituting Example 170B for
2-fluoro-6-iodobenzonitrile in Example 1A.
Example 170D
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)pheny-
l]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide
The desired product was prepared as the trifluoroacetate salt by
substituting Example 170C for Example 152B in Example 152C. MS
(APCI(+)) m/e 513 (M+H).sup.+; NMR (300 MHz, DMSO-d.sub.6) .delta.
2.28 (s, 3H) 2.99 (s, 3H) 3.43 (q, J=5.76 Hz, 2H) 4.22 (t, J=5.42
Hz, 2H) 4.35 (s, 2H) 6.70 (d, J=7.46 Hz, 1H) 6.80 (d, J=7.80 Hz,
1H) 6.80-6.83 (m, 1H) 7.08-7.19 (m, 2H) 7.37 (d, J=8.81 Hz, 2H)
7.56 (d, J=8.81 Hz, 2H) 8.01 (dd, J=7.97, 1.86 Hz, 1H) 8.52 (d,
J=2.37 Hz, 1H) 9.17 (s, 1H) 11.77 (s, 1H).
Example 171
4-(1H-indol-5-yl)-1H-indazol-3-amine
The desired product was prepared by substituting 5-indolylboronic
acid and Example 1A for
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example
15F, respectively, in Example 15G. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 4.28 (s, 2H), 6.50 (ddd, J=3.05, 2.03, 0.68
Hz, 1H), 6.80 (dd, J=6.27, 1.53 Hz, 1H), 7.18 (dd, J=8.14, 1.70 Hz,
1H), 7.25 (m, 2H), 7.43 (m, 1H), 7.51 (d, J=8.14 Hz, 1H), 7.60 (m,
1H), 11.23 (s, 1H), 11.63 (s, 1H); MS (ESI(+)) m/e 249
(M+H).sup.+.
Example 172
N-{4-[3-amino-1-(2-methoxyethyl).sup.-1H-indazol-4-yl]phenyl}-N'-(2-fluoro-
-5-methylphenyl)urea
Examples 172A and 172B
2-[4-iodo-2-(2-methoxyethyl).sup.-2H-indazol-3-yl]-1H-isoindole-1,3(2H).su-
p.-dione and
2-[4-iodo-1-(2-methoxyethyl).sup.-1H-indazol-3-yl]-1H-isoindole-1,3(2H).su-
p.-dione
A mixture of Example 162A (1.2 g, 3.1 mmol),
1-bromo-2-methoxyethane (0.35 mL, 3.7 mmol) and K.sub.2CO.sub.3
(857 mg, 6.2 mmol) in DMF (15 mL) wa stirred overnight at rt, then
concentrated to dryness. The residue was partitioned between EtOAc
and H.sub.2O. The extract was dried (Na.sub.2SO.sub.4) and
concentrated, and the residue was purified by flash chromatography
on silica gel, eluting with 2% MeOH/CH.sub.2Cl.sub.2. The product
was obtained as a mixture of Examples 172A and 172B
(.about.3:1).
Example 172C and 172D
4-iodo-1-(2-methoxyethyl).sup.-1H-indazol-3-amine and
4-iodo-2-(2-methoxyethyl).sup.-1H-indazol-3-amine
A mixture of the isomers 172A and 172B (970 mg, 2.2 mmol) was
dissolved in EtOH (10 mL) and the solution was chilled to 0.degree.
C. and treated dropwise with hydrazine monohydrate (0.58 mL), then
stirred for 3 h at rt. The mixture was concentrated to dryness and
the residue was purified by flash chromatography on silica gel,
eluting with 0-4% MeOH/CH.sub.2Cl.sub.2. A mixture of isomers 172C
and 172D was obtained. MS (ESI(+)) m/e 317.8 (M+H).sup.+.
Example 172E and 172F
4-(4-aminophenyl).sup.-1-(2-methoxyethyl).sup.-1H-indazol-3-amine
and
4-(4-aminophenyl).sup.-2-(2-methoxyethyl).sup.-1H-indazol-3-amine
A mixture of Examples 172E and 172F was prepared by substituting a
mixture of Examples 172C and 172D for Example 15F in Example 15G.
MS (ESI(+)) m/e 283.0 (M+H).sup.+.
Example 172G
N-{-4-[3-amino-1-(2-methoxyethyl).sup.-1H-indazol-4-yl]phenyl}-N'-(2-fluor-
o-5-methylphenyl)urea
The desired product was obtained by substituting a mixture of
Examples 172E and 172F for Example 15G and
1-fluoro-2-isocyanato-4-methylbenzene for
1-fluoro-3-isocyanatobenzene in Example 15H. Additionally, DMF was
used in place of CH.sub.2Cl.sub.2. The mixture was concentrated and
the residue was purified by preparative HPLC as in example 3 to
provide the desired product as the trifluoroacetate salt. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.28 (s, 3H) 3.21 (s, 3H)
3.69 (t, J=5.4 Hz, 2H) 4.32 (t, J=5.4 Hz, 2H) 6.79-6.84 (m, 2H)
7.12 (dd, J=11.4, 8.3 Hz, 1H) 7.31 (dd, J=8.5, 6.8 Hz, 1H)
7.38-7.43 (m, 3H) 7.59 (d, J=8.5 Hz, 2H) 8.01 (dd, J=7.8, 2.0 Hz,
1H) 8.54 (d, J=2.4 Hz, 1H) 9.21 (s, 1H) MS (ESI(+)) m/e 434.0
(M+H).sup.+.
Example 174
N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethoxy]-1H--
indazol-4-yl}phenyl).sup.-N'-(3,5-dimethylphenyl)urea
The desired product was prepared by substituting Example 145A and
1-isocyanato-3,5-dimethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The
product was purified by preparative HPLC as in example 3. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.27 (s, 6H) 2.24 (s, 6H)
2.81 (s, 3H) 3.83 (t, J=6.4 Hz, 2H) 4.35 (t, J=6.4 Hz, 2H) 6.62 (s,
1H) 6.68 (d, J=7.8 Hz, 1H) 6.83 (d, J=7.8 Hz, 1H) 7.09 (s, 2H) 7.34
(d, J=8.8 Hz, 2H) 7.55 (d, J=8.8 Hz, 2H) 8.54 (s, 1H) 8.74 (s, 1H)
11.75-11.85 (br. s., 1H) MS (ESI(+)) m/e 556.3 (M+H).sup.+.
Example 175
N-[4-(3-amino-1H-indazol-4-yl).sup.-2,6-dimethylphenyl]-N'-(2-fluoro-5-met-
hylphenyl)urea
The desired product was prepared by substituting
4-bromo-2,6-dimethylaniline for 4-bromo-2-ethylaniline in Examples
149A-C. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.25 (s,
3H) 2.30 (s, 6H) 6.77-6.80 (m, 1H) 6.87 (dd, J=5.8, 2.4 Hz, 1H)
7.10 (dd, J=11.5, 8.5 Hz, 1H) 7.20 (s, 2H) 7.33 (s, 1H) 7.35 (d.
J=3.4 Hz, 1H) 7.98 (d, J=6.8 Hz, 1H) 8.23 (s, 1H) 8.54-8.65 (br.
s., 1H) 11.99-12.20 (br. s., 1H) MS (ESI(+)) m/e 404.2
(M+H).sup.+.
Example 176
N-[4-(3-amino-1H-indazol-4-yl).sup.-2,6-dimethylphenyl]-N'-[3-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting
1-isocyanato-3-(trifluoromethyl)benzene and
4-bromo-2,6-dimethylaniline for
1-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylaniline,
respectively, in Examples 149A-C. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 2.30 (s, 6H) 6.84 (dd, J=5.3, 2.5 Hz, 1H)
7.21 (s, 2H) 7.27-7.32 (m, 3H) 7.50 (t, J=8.0 Hz, 1H) 7.62 (d,
J=8.5 Hz, 1H) 7.96 (s, 1H) 8.03 (s, 1H) 9.17 (s, 1H) 11.88-11.99
(m, 1H) MS (ESI(+)) m/e 440.2 (M+H).sup.+.
##STR00012##
Example 177
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-hydroxyphenyl)urea
The desired product was prepared by substituting
4-iodo-1-isocyanatobenzene and 3-hydroxyaniline for
1-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylaniline,
respectively, in Examples 149A-C. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 6.38 (ddd, J=8.1, 2.3, 0.9 Hz, 1H) 6.82
(ddd, J=8.0, 2.0, 0.9 Hz, 1H) 6.86 (dd, J=6.4, 1.7 Hz, 1H)
7.03-7.08 (m, 2H) 7.29-7.35 (m, 2H) 7.40 (d, J=8.5 Hz, 2H) 7.59 (d,
J=8.8 Hz, 2H) 8.65 (s, 1H) 8.80 (s, 1H) 9.12-9.53 (br. s., 1H)
11.80-12.39 (br. s., 1H) MS (ESI(+)) m/e 360.2 (M+H).sup.+.
Example 178
N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]methanesulfonamide
Example 178A
N-(2-{[3-amino-4-(4-aminophenyl).sup.-1H-indazol-7-yl]oxy}ethyl)methanesul-
fonamide
The desired product was prepared by substituting Example 170C and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples
1A and 1B, respectively, in Example 1C.
Example 178B
N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]methanesulfonamide
The desired product was prepared by substituting Example 178A and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H) 2.99 (s, 3H)
3.44 (q, J=5.8 Hz, 2H) 4.23 (t, J=5.4 Hz, 2H) 6.73 (d, J=7.8 Hz,
1H) 6.80 (d, J=7.8 Hz, 1H) 6.84 (d, J=7.8 Hz, 1H) 7.12-7.19 (m, 2H)
7.25 (d, J=8.1 Hz, 1H) 7.31 (s, 1H) 7.36 (d, J=8.5 Hz, 2 H) 7.56
(d, J=8.5 Hz, 2H) 8.63 (s, 1H) 8.77 (s, 1H), 11.91-12.07 (br. s.,
1H) MS (ESI(+)) m/e 495.1 (M+H).sup.+.
Example 179
N-{2-[(3-amino-4-{-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl-
)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide
The desired product was prepared by substituting Example 178A and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.99 (s, 3H) 3.44
(q, J=6.1 Hz, 2H) 4.22 (t, J=5.4 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H)
6.82 (d, J=7.8 Hz, 1H) 7.17 (t, J=6.1 Hz, 1H) 7.38-7.42 (m, 3H)
7.48-7.54 (m, 1H) 7.58 (d, J=8.8 Hz, 2H) 8.65 (dd, J=7.5, 2.0 Hz,
1H) 8.94 (d, J=3.1 Hz, 1H) 9.29 (s, 1H) 11.87 (s, 1H) MS (ESI(+))
m/e 567.2 (M+H).sup.+.
Example 180
N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]methanesulfonamide
The desired product was prepared by substituting Example 178A and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 2.99 (s, 3H) 3.43 (q, J=5.8 Hz,
2H) 4.22 (t, J=5.4 Hz, 2H) 6.71 (d, J=7.8 Hz, 1H) 6.81 (d, J=7.8
Hz, 1H) 7.03 (dt, J=6.7, 2.3 Hz, 1H) 7.15-7.19 (m, 1H) 7.27-7.32
(m, 2H) 7.37 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 7.73 (t,
J=1.9 Hz, 1H) 8.86 (s, 1H) 8.93 (s, 1H) 11.84 (s, 1H) MS (ESI(+))
m/e 515.1 (M+H).sup.+.
Example 181
N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phe-
nyl}-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide
The desired product was prepared by substituting Example 178A and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.99 (s, 3H) 3.43 (q, J=5.8
Hz, 2H) 4.22 (t, J=5.4 Hz, 2H) 6.71 (d, J=7.5 Hz, 1H) 6.81 (d,
J=7.8 Hz, 1H) 7.17 (t, J=5.8 Hz, 1H) 7.30-7.34 (m, 1H) 7.37 (d,
J=8.5 Hz, 2H) 7.50-7.61 (m, 4H) 8.04 (t, J=2.2 Hz, 1H) 8.91 (s, 1H)
9.09 (s, 1H) 11.82 (s, 1H) MS (ESI(-)) m/e 547.1
Example 182
N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea
Example 182A
6-bromo-1H-indazol-3-amine
The desired product was prepared by substituting
4-bromo-2-fluorobenzonitrile for 2-fluoro-6-iodobenzonitrile in
Example 1A. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.44
(s, 2H) 7.02 (dd, J=8.48, 1.70 Hz, 1H) 7.41 (d, J=1.70 Hz, 1H) 7.63
(d, J=8.48 Hz, 1H) 11.49 (s, 1H).
Example 182C
N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 182A and
1B for 1A and 5A respectively, in Example 513. MS (ESI(+) Q1MS m/z
358 (M+H).sup.+; .sup.1H NMR (500 MHz, DMSO-D.sub.6) .delta. ppm
2.29 (s, 3H) 5.34 (s, 2H) 6.79 (d, J=7.32 Hz, 1H) 7.15-7.20 (m, 2H)
7.25 (d, J=8.24 Hz, 1H) 7.31 (s, 1H) 7.38 (s, 1H) 7.55 (d, J=8.85
Hz, 2H) 7.62 (m, 2H) 7.72 (d, J=8.54 Hz, 1H) 8.75 (s, 1H) 8.89 (s,
1H) 11.38 (s, 1H)
Example 183
3-amino-N-(3-methylphenyl)-6-[4-({[(3-methylphenyl)amino]carbonyl}amino)ph-
enyl]-1H-indazole-1-carboxamide
Example 183A
6-(4-aminophenyl)-1H-indazol-3-amine
The desired product was prepared by substituting Example 182A for
Example 1A and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Example
5A in Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
5.19 (s, 2H) 5.27 (s, 2H) 6.64 (d, J=8.48 Hz, 2H) 7.10 (dd, J=8.48,
1.36 Hz, 1H) 7.25 (s, 1H) 7.37 (d, J=8.48 Hz, 2H) 7.64 (d, J=8.48
Hz, 1H) 11.25 (s, 1H).
Example 183B
3-amino-N-(3-methylphenyl)-6-[4-({[(3-methylphenyl)amino]carbonyl}amino)ph-
enyl]-1H-indazole-1-carboxamide
The desired product was prepared by substituting example 183A and
1-isocyanato-3-methylbenzene for 15 G and
1-fluoro-3-isocyanatobenzene, respectively in example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H) 2.32 (s, 3H)
6.37 (s, 2H) 6.80 (d, J=7.1 Hz, 1H) 6.91 (d, J=7.5 Hz, 1H) 7.17 (t,
J=7.8 Hz, 1H) 7.22 (t, J=7.8 Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.33
(s, 1H) 7.46-7.50 (m, 1H) 7.55-7.61 (m, 4H) 7.68 (d, J=8.8 Hz, 2H)
7.95 (d, J=8.1 Hz, 1H) 8.39 (d, J=0.7 Hz, 1H) 8.62 (s, 1H) 8.83 (s,
1H) 9.37 (s, 1H) MS (ESI(+)) m/e 490.0 (M+H).sup.+.
Example 184
N-[3-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
Example 184A
N-(3-methylphenyl)-N'-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl]urea
The desired product was prepared by substituting
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example
1B. MS (ESI(+)) m/e 352.9 (M+H).sup.+.
Example 184B
N-[3-(3-amino-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 184A for
Example 5A in Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.27 (s, 3H) 6.78-6.83 (m, 2H) 7.05-7.09 (m, 1 H) 7.15
(t, J=7.8 Hz, 1H) 7.22 (d, J=8.1 Hz, 1H) 7.28-7.31 (m, 3H)
7.38-7.43 (m, 2H) 7.63 (s, 1H) 8.63 (s, 1H) 8.81 (s, 1H) 11.74 (s,
1H) MS (ESI(+)) m/e 358.1 (M+H).sup.+.
Example 185
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
Example 185A
4-iodo-7-methyl-1H-indazol-3-amine
The desired compound was prepared by substituting Example 15C for
2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 273.8
(M+H).sup.+.
Example 185B
4-(4-aminophenyl)-7-methyl-1H-indazol-3-amine
The desired product was prepared by substituting Example 185A and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples
1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 239.0
(M+H).sup.+.
Example 185C
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 185B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H) 2.42 (s, 3H)
6.70 (d, J=7.1 Hz, 1H) 6.80 (d, J=7.5 Hz, 1H) 7.05 (dd, J=7.1, 1.0
Hz, 1H) 7.16 (t, J=7.8 Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.32 (s, 1H)
7.36 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 8.63 (s, 1H) 8.77 (s,
1H) 11.75 (s, 1H) MS (ESI(+)) m/e 371.6 (M+H).sup.+.
Example 186
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared by substituting Example 185B and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.45 (s, 3H) 6.80 (d, J=7.1
Hz, 1H) 7.00-7.06 (m, 1H) 7.15 (dd, J=7.1, 1.0 Hz, 1H) 7.28-7.32
(m, 2H) 7.39 (d, J=8.8 Hz, 2H) 7.60 (d, J=8.8 Hz, 2H) 7.73-7.75 (m,
1H) 8.98 (s, 1H) 9.01 (s, 1H) 12.01-12.46 (br. s., 1H) MS (ESI(+))
m/e 382.0 (M+H).sup.+.
Example 187
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phen-
yl]urea
The desired product was prepared by substituting Example 185B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.43 (s, 3H) 6.73 (d, J=7.1
Hz, 1H) 7.08 (d, J=7.1 Hz, 1H) 7.32 (d, J=8.1 Hz, 1H) 7.39 (d,
J=8.5 Hz, 2H) 7.53 (t, J=7.8 Hz, 1H) 7.58-7.61 (m, 3H) 8.04 (s, 1H)
8.94 (s, 1H) 9.11 (s, 1H) 11.87 (s, 1H) MS (ESI(+)) m/e 426.0
(M+H).sup.+.
Example 188
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting Example 185B and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.43 (s, 3H) 6.71 (d, J=7.1
Hz, 1H) 7.06 (d, J=7.8 Hz, 1H) 7.38-7.43 (m, 3H) 7.48-7.55 (m, 1H)
7.59 (d, J=8.5 Hz, 2H) 8.65 (dd, J=7.3, 2.2 Hz, 1H) 8.95 (d, J=2.7
Hz, 1H) 9.30 (s, 1H) 11.78 (s, 1H) MS (ESI(+)) m/e 444.1
(M+H).sup.+.
Example 189
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
The desired product was prepared by substituting Example 185B and
1-bromo-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.44 (s, 3H) 6.76 (d, J=7.1
Hz, 1H) 7.11 (dd, J=7.3, 0.9 Hz, 1H) 7.16 (ddd, J=7.8, 2.0, 1.0 Hz,
1H) 7.25 (t, J=8.0 Hz, 1H) 7.33 (ddd, J=8.1, 2.0, 1.0 Hz, 1H) 7.39
(d, J=8.5 Hz, 2H) 7.59 (d, J=8.8 Hz, 2H) 7.88 (t, J=1.9 Hz, 1H)
8.94 (s, 1H) 8.97 (s, 1H) 12.06 (s, 1H) MS (ESI(+)) m/e 463.0,
438.0 (M+H).sup.+.
Example 190
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
The desired product was prepared by substituting Example 185B for
Example 15G in Example 15H. Additionally, DMF was used in place of
CH.sub.2Cl.sub.2. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
2.45 (s, 3H) 6.76-6.82 (m, 2H) 7.13-7.17 (m, 2H) 7.32 (td, J=8.5,
6.8 Hz, 1H) 7.39 (d, J=8.8 Hz, 2H) 7.52 (dt, J=12.1, 2.3 Hz, 1H)
7.60 (d, J=8.5 Hz, 2H) 8.96 (s, 1H) 9.03 (s, 1H) 12.08-12.44 (br.
s., 1H) MS (ESI(+)) ink 376.1 (M+H).sup.+.
Example 191
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
The desired product was prepared by substituting Example 185B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.28 (s, 3H) 2.45 (s, 3H)
6.78 (d, J=6.8 Hz, 1H) 6.79-6.84 (m, 1H) 7.08-7.15 (m, 2H) 7.39 (d,
J=8.5 Hz, 2H) 7.59 (d, J=8.8 Hz, 2H) 8.01 (dd, J=7.8, 1.7 Hz, 1H)
8.53 (d, J=2.4 Hz, 1H) 9.21 (s, 1H) 12.00-12.33 (br. s., 1H) MS
(ESI(+)) ink 390.0 (M+H).sup.+.
Example 192
N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea
The desired product was prepared by substituting Example 185B and
3-isocyanatobenzonitrile for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.44 (s, 3H) 6.77 (d, J=7.1
Hz, 1H) 7.12 (dd, J=7.1, 1.0 Hz, 1H) 7.40 (d, J=8.5 Hz, 2H) 7.43
(dt, J=7.8, 1.4 Hz, 1H) 7.51 (t, J=8.0 Hz, 1H) 7.60 (d, J=8.5 Hz,
2H) 7.70 (ddd, J=8.3, 2.2, 1.0 Hz, 1H) 8.01 (t, J=1.7 Hz, 1H) 9.05
(s, 1H) 9.14 (s, 1H) 11.98-12.22 (br. s., 1H) MS m/e (ESI(+)) 383.1
(M+H).sup.+.
Example 193
N-[4-(3-amino-1H-indazol-4-yl)-2-(trifluoromethoxy)phenyl]-N'-(2-fluoro-5--
methylphenyl)urea
The desired product was prepared by substituting
4-bromo-2-(trifluoromethoxy)aniline for 4-bromo-2-ethylaniline in
Examples 149A-C. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
2.29 (s, 3H) 6.82-6.91 (m, 2H) 7.14 (dd, J=11.5, 8.1 Hz, 1H) 7.32
(d, J=1.0 Hz, 1H) 7.34 (s, 1H) 7.47-7.52 (m, 2H) 8.03 (dd, J=8.0,
1.9 Hz, 1H) 8.42 (d, J=8.8 Hz, 1H) 9.03 (s, 1H) 9.24 (d, J=2.4 Hz,
1H) 11.83-12.13 (br. s., 1H) MS (ESI(+)) m/e 460.1 (M+H).sup.+.
Example 194
N-[5-(3-amino-1H-indazol-4-yl)pyridin-2-yl]-N'-(2-fluoro-5-methylphenyl)ur-
ea
Example 194A
N-(5-bromopyridin-2-yl)-N'-(2-fluoro-5-methylphenyl)urea
The desired product was prepared by substituting
2-amino-5-bromopyridine and 1-fluoro-2-isocyanato-4-methylbenzene
for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)) m/e 324.0 (M+H).sup.+.
Example 194B
N-[5-(3-amino-1H-indazol-4-yl)pyridin-2-yl]-N'-(2-fluoro-5-methylphenyl)ur-
ea
The desired product was prepared by substituting Example 194A for
Example 44A in Example 44B. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.30 (s, 3H) 6.83-6.92 (m, 2H) 7.15 (dd, J=11.2, 8.5
Hz, 1H) 7.34 (s, 1H) 7.35 (s, 1H) 7.54 (d, J=8.5 Hz, 1H) 7.90 (dd,
J=8.7, 2.5 Hz, 1H) 8.07 (dd, J=7.5, 2.0 Hz, 1H) 8.38 (d, J=2.4 Hz,
1H) 9.95 (s, 1H) 10.88 (s, 1H) 12.02 (s, 1H) MS (ESI(+)) m/e 377.1
(M+H).sup.+.
Example 195
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluorome-
thyl)phenyl]urea
Example 195A
7-fluoro-4-iodo-1H-indazol-3-amine
The desired product was prepared by substituting Example 26A for
2-fluoro-6-iodobenzonitrile in Example 1A.
Example 195B
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting Example 195A for
Example 1A and
N-(2-fluoro-5-(trifluoromethyl)phenyl).sup.-N'-[4-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example
5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 6.74 (dd,
J=7.8, 4.1 Hz, 1H) 7.13 (dd, J=11.5, 7.8 Hz, 1H) 7.37-7.43 (m, 3H)
7.51 (dd, J=10.9, 8.5 Hz, 1H) 7.61 (d, J=8.5 Hz, 2H) 8.64 (dd,
J=7.3, 2.2 Hz, 1H) 8.96 (d, J=3.1 Hz, 1H) 9.32 (s, 1H) 12.25 (s,
1H) MS (ESI(+)) mile 448.0 (M+H).sup.+.
Example 196
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea
The desired product was prepared by substituting Example 195A for
Example 1A and
N-(4-fluorophenyl)N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl]urea for Example 5A in Example 5B. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 6.74 (dd, J=7.8, 4.1 Hz, 1H) 7.11 (dd,
J=7.8, 1.4 Hz, 1H) 7.15 (d, J=8.5 Hz, 2H) 7.37 (d, J=8.5 Hz, 2H)
7.49 (dd, J=9.3, 4.9 Hz, 2H) 7.58 (d, J=8.5 Hz, 2H) 8.77 (s, 1H)
8.83 (s, 1H) 12.29 (s, 1H) MS (ESI(+)) m/e 380.0 (M+H).sup.+.
Example 197
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea
The desired product was prepared by substituting Example 195A for
Example 1A and
N-(2-fluorophenyl)N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl]urea for Example 5A in Example 5B. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 6.98-7.06 (m, 1H) 7.14 (dd, J=11.2, 7.8
Hz, 1H) 7.16 (dt, J=7.5, 1.4 Hz, 1H) 7.25 (ddd, J=11.5, 8.1, 1.4
Hz, 1H) 7.33-7.38 (m, 1H) 7.39 (d, J=8.5 Hz, 2H) 7.59 (d, J=8.5 Hz,
2H) 8.17 (td, J=8.3, 1.7 Hz, 1H) 8.61 (d, J=2.7 Hz, 1H) 9.23 (s,
1H) 11.99-12.62 (br. s., 1H) MS (ESI(+)) mile 380.0
(M+H).sup.+.
Example 198
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl-
)urea
The desired product was prepared by substituting Example 195A for
Example 1A and
N-(3-fluoro-4-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2--
dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B. NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 2.17 (d, J=1.4 Hz, 3H) 6.73
(dd, J=7.8, 4.1 Hz, 1H) 7.05 (dd, J=8.3, 2.2 Hz, 1H) 7.13 (dd,
J=11.2, 7.8 Hz, 1H) 7.17 (t, J=8.7 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H)
7.45 (dd, J=12.5, 2.0 Hz, 1H) 7.58 (d, J=8.5 Hz, 2 H) 8.84 (s, 1H)
8.86 (s, 1H) 12.11-12.41 (br. s., 1H) MS (ESI(+)) m/e 394.1
(M+H).sup.+.
Example 199
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-phenylurea
The desired product was prepared by substituting Example 195A for
Example 1A and
N-phenyl-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
]urea for Example 5A in Example 5B. NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 634 (dd, J=7.8, 4.4 Hz, 1H) 6.98 (t, J=7.3 Hz, 1H) 7.13
(dd, J=11.2, 7.8 Hz, 1H) 7.26-7.32 (m, 2H) 7.37 (d, J=8.5 Hz, 2H)
7.46-7.49 (m, 2H) 7.59 (d, J=8.5 Hz, 2H) 8.74 (s, 1H) 8.84 (s, 1H)
11.99-12.59 (br. s., 1H) MS (ESI(+)) m/e 362.0 (M+H).sup.+.
Example 200
N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide
Example 200A
N-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}-1,1,1-trifluoromethanesul-
fonamide
The desired product was prepared by substituting
trifluoromethanesulfonic anhydride for methanesulfonyl chloride in
Example 170B.
Example 200B
N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide
The desired product was prepared by substituting Example 200A and
Example 1B for Example 1A and Example 5A, respectively, in Example
5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H)
3.65 (q, J=6.1 Hz, 2H) 4.24 (t, J=5.3 Hz, 2H) 6.73 (d, J=7.8 Hz,
1H) 6.80 (d, J=6.8 Hz, 1H) 6.85 (d, J=7.8 Hz, 1H) 7.16 (t, J=7.6
Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.31 (s, 1H) 7.36 (d, J=8.5 Hz, 2H)
7.57 (d, J=8.5 Hz, 2H) 8.63 (s, 1H) 8.78 (s, 1H) 9.52 (t, J=5.6 Hz,
1H) 11.83 (s, 1H) MS (ESI(+)) m/e 549.1 (M+H).sup.+.
Example 201
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
The desired product was prepared by substituting
1-fluoro-2-isocyanato-4-methylbenzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. .sup.1H NMR (300
MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H) 6.80-6.87 (m, 2H) 7.13
(dd, J=11.4, 8.3 Hz, 1H) 7.26-7.40 (m, 4H) 8.04 (dd, J=8.1, 1.7 Hz,
1H) 8.32 (t, J=8.5 Hz, 1H) 9.04 (d, J=2.4 Hz, 1H) 9.16 (d, J=2.7
Hz, 1H) 11.90 (s, 1H) MS (ESI(+)) m/e 394.2 (M+H).sup.+.
Example 202
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethyl)phen-
yl]urea
The desired product was prepared by substituting
N-(4-fluoro-3-trifluoromethylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,-
2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 6.83 (dd, J=5.8,
2.3 Hz, 1H) 7.27-7.34 (m, 2H) 7.40-7.48 (m, 3H) 7.61 (d, J=8.8 Hz,
2H) 7.63-7.69 (m, 1H) 8.03 (dd, J=6.4, 2.7 Hz, 1H) 8.99 (s, 1H)
9.13 (s, 1H) 11.94 (s, 1H) MS (ESI(+)) m/e 430.0 (M+H).sup.+.
Example 203
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-3-(trifluoromethyl)phen-
yl]urea
The desired product was prepared by substituting
N-(2-fluoro-3-trifluoromethylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,-
2-dioxaborolan-2-yl)phenyl]urea for Example 5A in Example 5B.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 6.85 (dd, J=5.8,
2.0 Hz, 1H) 7.29-7.39 (m, 4H) 7.43 (d, J=8.5 Hz, 2H) 7.62 (d, J=8.5
Hz, 2H) 8.45-8.50 (m, 1H) 8.90 (d, J=2.7 Hz, 1H) 9.31 (s, 1H) 12.01
(m, 1H) MS (ESI(+)) m/e 430.1 (M+H).sup.+.
Example 204
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(4-bromo-2-fluorophenyl)urea
The desired product was prepared by substituting
N-(4-bromo-2-fluorophenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)phenyl]urea for Example 5A in Example 5B. .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 6.83 (dd, J=5.8, 2.0 Hz, 1H)
7.30 (d, J=0.7 Hz, 1H) 7.31 (dd, J=13.2, 8.1 Hz, 1H) 7.37 (ddd,
J=8.8, 2.0, 1.4 Hz, 1H) 7.42 (d, J=8.8 Hz, 2H) 7.56-7.61 (m, 3H)
8.16 (t, J=8.8 Hz, 1H) 8.71 (d, J=2.4 Hz, 1H) 9.25 (s, 1H) 11.97
(s, 1H) MS (ESI(+)) m/e 440.0, 440.9 (M+H).sup.+.
Example 205
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(5-fluoro-2-methylphenyl)urea
The desired product was prepared by substituting
N-(5-fluoro-2-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for Example 5A in Example 5B. .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 2.24 (s, 3H) 6.76 (td, J=8.5,
2.7 Hz, 1H) 6.87 (dd, J=6.1, 1.7 Hz, 1H) 7.16-7.24 (m, 1H)
7.30-7.38 (m, 2H) 7.43 (d, J=8.5 Hz, 2H) 7.62 (d, J=8.5 Hz, 2H)
7.87 (dd, J=12.2, 2.7 Hz, 1H) 8.12 (s, 1H) 9.34 (s, 1H) 11.94-12.25
(br. s., 1 H) MS (ESI(+)) m/e 376.1 (M+H).sup.+.
Example 206
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl)urea
The desired product was prepared by substituting
N-(4-fluoro-3-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for Example 5A in Example 5B. .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 2.22 (d, J=1.7 Hz, 3H) 6.84
(dd, J=6.1, 1.7 Hz, 1H) 7.06 (t, J=9.2 Hz, 1H) 7.25-7.34 (m, 3H)
7.37-7.41 (m, 3H) 7.59 (d, J=8.5 Hz, 2H) 8.69 (s, 1H) 8.84 (s, 1H)
11.86-12.20 (br. s., 1H) MS (ESI(+)) m/e 376.1 (M+H).sup.+.
Example 207
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-pheny-
lurea
Example 207A
2-fluoro-6-iodo-3-(3-morpholin-4-ylpropoxy)benzonitrile
The desired product was prepared by substituting
3-(4-morpholinyl).sup.-propan-1-ol for 2-(4-morpholinyl)ethanol in
Example 75A. MS (ESI(+)) m/e 391 (M+H).sup.+.
Example 207B
4-(4-aminophenyl)-7-(3-morpholin-4-ylpropoxy)-1H-indazol-3-amine
The desired product was prepared by substituting Example 207A for
Example 15E in Examples 15F-G.
Example 207C
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-phen-
ylurea
The desired product was prepared by substituting Example 207B and
isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene,
respectively, in Example 15H. .sup.1H NMR (500 MHz, DMSO-D.sub.6)
.delta. ppm 2.18-2.23 (m, 2H) 3.08-3.20 (m, 4H) 3.51-3.53 (m, 2H)
3.65-3.70 (m, 2H) 4.02-4.05 (m, 2H) 4.24 (t, J=5.9 Hz, 2H) 6.72 (d,
J=7.8 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H) 6.98 (t, J=7.3 Hz, 1H)
7.27-7.31 (m, 2H) 7.35 (d, J=8.4 Hz, 2H) 7.48 (d, J=7.8 Hz, 2H)
7.57 (d, J=8.4 Hz, 2H) 8.76 (s, 1H) 8.84 (s, 1H) 9.68 (s, 1H) 11.86
(s, 1H) MS (ESI(+)) m/e 487.2 (M+H).sup.+.
Example 208
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-f-
luorophenyl)urea
The desired product was prepared by substituting Example 207 for
Example 15G in Example 15H. .sup.1H NMR (500 MHz, DMSO-D.sub.6)
.delta. ppm 2.18-2.23 (m, 2H) 3.08-3.18 (m, 4H) 3.51-3.53 (m, 2H)
3.65-3.70 (m, 2H) 4.02-4.05 (m, 2H) 4.23 (t, J=5.8 Hz, 2H) 6.72 (d,
J=7.8 Hz, 1H) 6.78 (dt, J=8.1, 2.5 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H)
7.15 (dd, J=8.1, 1.3 Hz, 1H) 7.31 (dd, J=15.3, 8.4 Hz, 1H) 7.36 (d,
J=8.7 Hz, 2H) 7.52 (dt, J=11.9, 2.2 Hz, 1H) 7.57 (d, J=8.7 Hz, 2H)
8.96 (s, 1H) 9.06 (s, 1H) 9.71 (s, 1H) 11.86 (s, 1H) MS (ESI(+))
m/e 505.1 (M+H).sup.+.
Example 209
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fl-
uoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 207B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 2.19-2.24 (m, 2H) 2.28 (s,
3H) 3.08-3.18 (m, 2H) 3.42-3.45 (m, 2H) 3.50-3.55 (m, 2H) 3.68-3.72
(m, 2H) 4.03-4.08 (m, 2H) 4.24 (t, J=5.8 Hz, 2H) 6.75 (d, J=7.8 Hz,
1H) 6.80-6.84 (m, 1H) 6.84 (d, J=7.8 Hz, 1H) 7.11 (dd, J=11.2, 8.4
Hz, 1H) 7.37 (d, J=8.4 Hz, 2H) 7.58 (d, J=8.4 Hz, 2H) 7.99 (dd,
J=7.8, 1.9 Hz, 1H) 8.56 (d, J=2.5 Hz, 1H) 9.24 (s, 1H) 9.76-10.28
(br. s., 1H) MS (ESI(+)) m/e 519.2 (M+H).sup.+.
Example 210
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-m-
ethylphenyl)urea
The desired product was prepared by substituting Example 207B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 2.19-2.23 (m, 2H) 2.29 (s,
3H) 3.08-3.17 (m, 2H) 3.43-3.51 (m, 4H) 3.66-3.70 (m, 2H) 4.02-4.05
(m, 2H) 4.24 (t, J=5.8 Hz, 2 H) 6.72 (d, J=7.8 Hz, 1H) 6.80 (d,
J=8.1 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H) 7.16 (t, J=7.6 Hz, 1H) 7.26
(d, J=8.1 Hz, 1H) 7.32 (s, 1H) 7.35 (d, J=8.4 Hz, 2H) 7.57 (d,
J=8.4 Hz, 2H) 8.70 (s, 1H) 8.84 (s, 1H) 9.72 (s, 1H) 11.88 (s, 1H)
MS (ESI(+)) m/e 501.2 (M+H).sup.+.
Example 211
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[2-f-
luoro-5-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 207B and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 2.18-2.24 (m, 2H)
3.08-3.18 (m, 2H) 3.42-3.45 (m, 2H) 3.51-3.57 (m, 2H) 3.65-3.71 (m,
2H) 4.02-4.05 (m, 2 H) 4.24 (t, J=5.8 Hz, 2H) 6.73 (d, J=7.5 Hz,
1H) 6.83 (d, J=7.8 Hz, 1H) 7.37-7.41 (m, 3H) 7.49-7.53 (m, 1H) 7.59
(d, J=8.7 Hz, 2H) 8.64 (dd, J=7.3, 2.0 Hz, 1H) 8.96 (d, J=2.8 Hz,
1H) 9.32 (s, 1H) 9.77 (s, 1H) 11.92 (s, 1H) MS (ESI(+)) in/e 573.1
(M+H).sup.+.
Example 212
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-ch-
lorophenyl)urea
The desired product was prepared by substituting Example 207B and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 2.18-2.23 (m, 2H) 3.08-3.18
(m, 4 H) 3.66-3.70 (m, 4H) 4.02-4.05 (m, 2H) 4.24 (t, J=5.8 Hz, 2H)
6.73 (d, J=7.8 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H) 7.01-7.03 (m, 1H)
7.29-7.33 (m, 2H) 7.36 (d, J=8.4 Hz, 2H) 7.58 (d, J=8.7 Hz, 2H)
7.74 (s, 1H) 9.00 (s, 1H) 9.07 (s, 1H) 9.74 (s, 1H) 11.89 (s, 1H)
MS (ESI(+)) in/e 521.1 (M+H).sup.+.
Example 213
N-{-4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(-
trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 207B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 2.18-2.24 (m, 2H) 3.08-3.19
(m, 4 H) 3.42-3.44 (m, 2H) 3.66-3.70 (m, 2H) 4.02-4.04 (m, 2H) 4.24
(t, J=5.8 Hz, 2H) 6.74 (d, J=7.8 Hz, 1H) 6.83 (d, J=7.8 Hz, 1H)
7.32 (d, J=7.8 Hz, 1H) 7.37 (d, J=8.4 Hz, 2H) 7.52 (t, J=8.0 Hz,
1H) 7.59-7.61 (m, 3H) 8.05 (s, 1H) 9.10 (s, 1H) 9.28 (s, 1H) 9.78
(s, 1H) 11.94 (s, 1H) MS (ESI(+)) m/e 555.2 (M+H).sup.+.
Example 214
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)pheny-
l]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide
The desired product was prepared by substituting Example 200A for
Example 1A in Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.28 (s, 3H) 3.65 (q, J=4.9 Hz, 2H) 4.24 (t, J=5.3 Hz,
2H) 6.73 (d, J=7.8 Hz, 1H) 6.78-6.82 (m, 1H) 6.84 (d, J=7.5 Hz, 1H)
7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5
Hz, 2H) 8.01 (dd, J=8.0, 2.2 Hz, 1H) 8.52 (d, J=2.7 Hz, 1H) 9.17
(s, 1H) 9.52 (t, J=5.8 Hz, 1H) 11.79 (s, 1H) MS (ESI(+)) 567.0 m/e
(M+H).sup.+.
Example 215
N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide
The desired product was prepared by substituting Example 200A and
N-(3-fluorophenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.65
(q, J=5.3 Hz, 2H) 4.23 (t, J=5.3 Hz, 2H) 6.71 (d, J=7.8 Hz, 1H)
6.78 (td, J=8.5, 2.0 Hz, 1H) 6.83 (d, J=7.8 Hz, 1H) 7.13 (m, 1H)
7.30 (m, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.44-7.54 (m, 1H) 7.57 (d,
J=8.5 Hz, 2H) 8.86 (s, 1H) 8.95 (s, 1H) 9.52 (t, J=5.3 Hz, 1H)
11.72 (s, 1H) MS (ESI(-)) m/e 550.9 (M-H).sup.-.
Example 216
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)pheny-
l]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide
Example 216A
N-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}benzenesulfonamide
The desired product was prepared by substituting phenylsulfonyl
chloride for methanesulfonyl chloride in Example 170B. MS (ESI(+))
m/e 459 (M+H).sup.+.
Example 216B
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)pheny-
l]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide
The desired product was prepared by substituting Example 216A and
N-(2-fluoro-5-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively,
in Example 5B. .sup.1H NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 2.28
(s, 3H) 3.26 (q, J=5.6 Hz, 2H) 4.08 (t, J=5.6 Hz, 2H) 6.67 (d,
J=7.8 Hz, 1H) 6.70 (d, J=7.8 Hz, 1H) 6.79-6.82 (m, 1H) 7.11 (dd,
J=11.2, 8.4 Hz, 1H) 7.36 (d, J=8.5 Hz, 2H) 7.55 (t, J=7.6 Hz, 2H)
7.56 (d, J=8.5 Hz, 2H) 7.61 (t, J=7.2 Hz, 1H) 7.78 (t, J=6.1 Hz,
1H) 7.84 (d, J=7.2 Hz, 2H) 8.00 (dd, J=8.0, 1.7 Hz, 1H) 8.50 (d,
J=2.5 Hz, 1H) 9.16 (s, 1H) 11.84 (s, 1H) MS (ESI(-)) m/e 573.2
(M-H).sup.-.
Example 217
N-{2-[(3-amino-4-{-4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]ph-
enyl}-1H-indazol-7-yl)oxy]ethyl}benzenesulfonamide
The desired product was prepared by substituting Example 216A and
N-(3-trifluoromethylphenyl)N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. .sup.1H NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 3.26
(q, J=5.8 Hz, 2H) 4.10 (t, J=5.6 Hz, 2H) 6.70 (d, J=7.8 Hz, 1H)
6.73 (d, J=7.8 Hz, 1H) 7.32 (d, J=7.5 Hz, 1H) 7.37 (d, J=8.4 Hz,
2H) 7.51-7.63 (m, 7H) 7.78 (t, J=6.1 Hz, 1H) 7.84 (d, J=8.7 Hz, 2H)
8.04 (s, 1H) 8.93 (s, 1H) 9.11 (s, 1H) 12.01 (s, 1H) MS (ESI(+))
m/e 611.1 (M+H).sup.+.
Example 218
N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]benzenesulfonamide
The desired product was prepared by substituting Example 216A and
N-(3-fluorophenyl).sup.31N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. .sup.1H NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 3.26
(q, J=5.6 Hz, 2H) 4.09 (t, J=5.6 Hz, 2H) 6.70 (d, J=7.8 Hz, 1H)
6.73 (d, J=7.8 Hz, 1H) 6.79 (td, J=8.4, 1.9 Hz, 1H) 7.14 (dd,
J=8.3, 1.1 Hz, 1H) 7.29-7.34 (m, 1H) 7.37 (d, J=8.7 Hz, 2H)
7.49-7.58 (m, 5H) 7.61 (t, J=7.3 Hz, 1H) 7.78 (t, J=6.1 Hz, 1H)
7.83-7.85 (m, J=8.4 Hz, 2H) 8.88 (s, 1H) 8.97 (s, 1H) 12.00 (s, 1H)
MS (ESI(-)) m/e 559.0 (M-H).sup.-.
Example 219
N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]benzenesulfonamide
The desired product was prepared by substituting Example 216A and
N-(3-chlorophenyl)N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl]urea for Example 1A and Example 5A, respectively, in Example 5B.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.26 (q, J=5.6 Hz,
2H) 4.10 (t, J=5.6 Hz, 2H) 6.70-6.75 (m, 2H) 7.03 (td, J=4.3, 2.2
Hz, 1H) 7.27-7.32 (m, 2 H) 7.37 (d, J=8.5 Hz, 2H) 7.52-7.64 (m, 5H)
7.74-7.75 (m, 1H) 7.78-7.85 (m, 3H) 8.92 (s, 1H) 8.98 (s, 1H) 12.09
(s, 1H) MS (ESI(+)) m/e 577.0 (M+H).sup.+.
Example 220
N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-flu-
oro-5-methylphenyl)urea
Example 220A
2-fluoro-3-formyl-6-iodobenzonitrile
LDA (24.3 mL, 2.0 M solution in THF) was added dropwise to a
stirred solution of 2-fluoro-6-iodobenzonitrile (10.0 g, 40.5 mmol)
in THF (200 mL) at -78.degree. C., and the mixture was stirred for
1 h. Methyl formate (5.0 mL, 81.0 mmol) was added via syringe and
the resulting mixture was stirred at -78.degree. C. for 30 min then
at rt for 1 h. H2O was added and the mixture was extracted with
EtOAc. The extracts were washed with brine, dried (MgSO4) and
concentrated. The residue was purified by flash chromatography on
silica gel eluting with 20-25% EtOAc/hexanes to give the desired
product (8.01 g). MS (ESI(+)) m/e 274.9 (M+H).sup.+.
Example 220B
2-fluoro-6-iodo-3-[(isopropylamino)methyl]benzonitrile
A solution of Example 220A (1.00 g, 3.6 mmol) in MeOH (15 mL) was
treated with isopropylamine (0.31 mL, 3.6 mmol) and sodium
cyanoborohydride (227 mg, 3.6 mmol), and the mixture was stirred
overnight at rt. HOAc (1 mL) was added and the reaction was stirred
for 5 h, then treated with 1N NaOH and extracted with EtOAc. The
extracts were washed with brine, dried (MgSO4) and concentrated.
The residue was purified by flash chromatography on silica gel
eluting with 8% MeOH/CH.sub.2Cl.sub.2 to give the desired product
(372 mg). MS (ESI(+)) m/e 318.9 (M+H).sup.+.
Example 220C
4-iodo-7-[(isopropylamino)methyl]-1H-indazol-3-amine
The desired product was prepared by substituting Example 220B for
2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 330.9
(M+H).sup.+.
Example 220D
N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-flu-
oro-5-methylphenyl)urea
The desired product was prepared by substituting Example 220C and
N-(2-fluoro-5-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively,
in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was
substituted for DME/water as solvent. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 1.33 (d, J=6.4 Hz, 6H) 2.28 (s, 3H)
3.39-3.51 (m, 1H) 4.39 (t, J=6.1 Hz, 2H) 6.79-6.84 (m, 1H) 6.90 (d,
J=7.1 Hz, 1H) 7.12 (dd, J=11.4, 8.3 Hz, 1H) 7.39-7.45 (m, 3H) 7.61
(d, J=8.5 Hz, 2H) 7.99 (dd, J=7.8, 2.0 Hz, 1H) 8.55 (d, J=2.4 Hz,
1H) 8.65-8.73 (m, 1H) 9.25 (s, 1H) 12.03 (s, 1H) MS (ESI(+)) m/e
447.1 (M+H).sup.+.
Example 221
N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-chl-
orophenyl)urea
The desired product was prepared by substituting Example 220C and
N-(3-chlorophenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted
for DME/water as solvent. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 1.33 (d, J=6.8 Hz, 6H) 3.37-3.49 (m, 1H) 4.38 (t, J=5.9
Hz, 2H) 6.90 (d, J=7.5 Hz, 1H) 7.03 (dt, J=6.4, 2.4 Hz, 1H)
7.28-7.35 (m, 2H) 7.39-7.45 (m, 3H) 7.62 (d, J=8.5 Hz, 2H)
7.74-7.75 (m, 1H) 8.63-8.73 (m, 2H) 9.03 (s, 1H) 9.04 (s, 1H) 12.03
(s, 1H) MS (ESI(+)) m/e 449.1 (M+H).sup.+.
Example 222
N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(tr-
ifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 220C and
N-(3-trifluoromethylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively,
in Example 5B. Additionally, toluene/EtOH/H.sub.2O (2:1:1) was
substituted for DME/water as solvent. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 1.33 (d, J=6.4 Hz, 6H) 3.39-3.51 (m, 1H)
4.39 (t, J=5.8 Hz, 2H) 6.91 (d, J=7.1 Hz, 1H) 7.32 (d, J=7.5 Hz,
1H) 7.39-7.45 (m, 3H) 7.53 (t, J=8.0 Hz, 1H) 7.59-7.66 (m, 3H) 8.05
(s, 1H) 8.67-8.73 (m, 2H) 9.14 (s, 1H) 9.28 (s, 1H) 12.05 (s, 1H)
MS (ESI(-)) m/e 481.0 (M-H).sup.-.
Example 223
N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-met-
hylphenyl)urea
The desired product was prepared by substituting Example 220C and
N-(3-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. Additionally, toluene/EtOH/H.sub.2O (2:1:1) was
substituted for DME/water as solvent. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 1.33 (d, J=6.4 Hz, 6H) 2.29 (s, 3H)
3.39-3.51 (m, 1H) 4.36-4.40 (m, 2H) 6.80 (d, J=7.8 Hz, 1H) 6.90 (d,
J=7.1 Hz, 1H) 7.17 (t, J=7.8 Hz, 1H) 7.26 (d, J=8.5 Hz, 1H) 7.32
(s, 1H) 7.39 (d, J=8.8 Hz, 2H) 7.44 (d, J=7.5 Hz, 1H) 7.62 (d,
J=8.8 Hz, 2H) 8.69 (m, 2H) 8.75 (s, 1H) 8.94 (s, 1H) 12.03 (s, 1H)
MS (ESI(+)) m/e 429.1 (M+H).sup.+.
Example 224
N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N'-(4-flu-
oro-3-methylphenyl)urea
The desired product was prepared by substituting Example 220C and
N-(4-fluoro-3-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively,
in Example 5B. Additionally, toluene/EtOH/H.sub.2O (2:1:1) was
substituted for DME/water as solvent. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 1.33 (d, J=6.4 Hz, 6H) 2.22 (d, J=1.7 Hz,
3H) 3.39-3.51 (m, 1H) 4.36-4.40 (m, 2H) 6.90 (d, J=7.1 Hz, 1H) 7.06
(t, J=9.2 Hz, 1H) 7.28 (ddd, J=8.4, 4.8, 3.1 Hz, 1H) 7.37-7.45 (m,
4H) 7.61 (d, J=8.5 Hz, 2H) 8.64-8.74 (m, 2H) 8.79 (s, 1H) 8.95 (s,
1H) 12.04 (s, 1H) MS (ESI(+)) m/e 447.1 (M+H).sup.+.
Example 225
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fl-
uoro-5-methylphenyl)urea
Example 225A
2-fluoro-3-(hydroxymethyl)-6-iodobenzonitrile
A solution of Example 220A (5.0 g, 18 mmol) in MeOH (100 mL) at
0.degree. C. was treated with NaBH4 (822 mg, 22 mmol) and the
mixture was stirred for 1 h at 0.degree. C. Acetone was added and
the mixture was stirred for 5 min, then concentrated to dryness.
The residue was partitioned between H2O and EtOAc. The extracts
were washed with brine, dried (MgSO4) and concentrated. The residue
was purified by flash chromatography on silica gel, eluting with
3:2 hexanes/EtOAc to give the desired product (3.14 g). Rf=0.38
(3:2 hexane:EtOAc).
Example 225B
3-[(4-chlorophenoxy)methyl]-2-fluoro-6-iodobenzonitrile
The desired product was prepared by substituting Example 225A and
4-chlorophenol for Example 68A and 2-(4-morpholinyl)ethanol,
respectively, in Example 75A. Additionally, diisopropyl
azodicarboxylate was substituted for DEAD. MS (ESI(-)) m/e 385.8
(M-H).sup.-.
Example 225C
7-[(4-chlorophenoxy)methyl]-4-iodo-1H-indazol-3-amine
The desired product was prepared by substituting Example 225B for
2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 399.9
(M+H).sup.+.
Example 225D
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(2-fl-
uoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 225C for
Example 1A and in Example 5B Additionally, toluene/EtOH/H2O (2:1:1)
was substituted for DME/water as solvent. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 2.28 (s, 3H) 5.33 (s, 2H) 6.79-6.83 (m, 2
H) 7.09 (d, J=9.2 Hz, 2H) 7.06-7.15 (m, 1H) 7.33-7.38 (m, 3H) 7.41
(d, J=8.5 Hz, 2H) 7.60 (d, J=8.5 Hz, 2H) 8.01 (dd, J=7.8, 2.0 Hz,
1H) 8.54 (d, J=2.7 Hz, 1H) 9.22 (s, 1H) 12.00 (s, 1H) MS (ESI(+))
m/e 516.1 (M+H).sup.+.
Example 226
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-ch-
lorophenyl)urea
The desired product was prepared by substituting Example 226C and
N-(3-chlorophenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted
for DME/water as solvent. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 5.33 (s, 2H) 6.82 (d, J=7.5 Hz, 1H) 7.01-7.05 (m, 1H)
7.08 (d, J=8.8 Hz, 2H) 7.28-7.32 (m, 2H) 7.33-7.38 (m, 3H) 7.41 (d,
J=8.8 Hz, 2H) 7.60 (d, J=8.8 Hz, 2H) 7.73-7.74 (m, 1H) 8.93 (s, 1H)
8.96 (s, 1 H) 12.01 (s, 1H) MS (ESI(+)) m/e 518.5 (M+H).sup.+.
Example 227
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-[3-(t-
rifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 225C and
N-(3-trifluoromethylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively,
in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was
substituted for DME/water as solvent. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 5.32 (s, 2H) 6.82 (d, J=7.1 Hz, 1H) 7.08
(d, J=8.8 Hz, 2H) 7.31-7.37 (m, 4H) 7.41 (d, J=8.5 Hz, 2H) 7.53 (t,
J=8.0 Hz, 1H) 7.59-7.63 (m, 3H) 8.04 (s, 1H) 8.96 (s, 1H) 9.11 (s,
1H) 11.96 (s, 1H) MS (ESI(+)) m/e 522.0 (M+H).sup.+.
Example 228
N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(3-me-
thylphenyl)urea
The desired product was prepared by substituting Example 225C and
N-(3-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was substituted
for DME/water as solvent. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.29 (s, 3H) 5.33 (s, 2H) 6.80 (d, J=7.5 Hz, 1H) 6.83
(d, J=7.1 Hz, 1H) 7.08 (d, J=8.8 Hz, 2H) 7.17 (t, J=7.8 Hz, 1H)
7.25 (d, J=8.5 Hz, 1H) 7.32 (s, 1H) 7.33-7.41 (m, 5H) 7.60 (d,
J=8.8 Hz, 2H) 8.65 (s, 1H) 8.82 (s, 1H) 12.08 (s, 1H) MS (ESI(+))
m/e 498.1 (M+H).sup.+.
Example 229
N-(4-{3-amino-7-[4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N'-(4-flu-
oro-3-methylphenyl)urea
The desired product was prepared by substituting Example 225C and
N-(4-fluoro-3-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for Example 1A and Example 5A, respectively,
in Example 5B. Additionally, toluene/EtOH/H2O (2:1:1) was
substituted for DME/water as solvent. .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 2.22 (d, J=1.7 Hz, 3H) 5.33 (s, 2H) 6.83
(d, J=7.1 Hz, 1H) 7.01-7.11 (m, 3H) 7.25-7.31 (m, 1H) 7.33-7.41 (m,
6H) 7.59 (d, J=8.8 Hz, 2H) 8.68 (s, 1H) 8.82 (s, 1H) 12.05 (s, 1H)
MS (ESI(+)) m/e 516.1 (M+H).sup.+.
Example 230
N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2--
fluoro-5-methylphenyl)urea
Example 230A
2-fluoro-6-iodo-3-[3-(1H-pyrrol-1-yl)propoxy]benzonitrile
The desired product was prepared by substituting
3-pyrrol-1-yl-propan-1-ol for 2-(4-morpholinyl)ethanol in Example
75A.
Example 230B
4-iodo-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-3-amine
The desired product was prepared by substituting Example 230A for
2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 383
(M+H).sup.+.
Example 230C
N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2--
fluoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 230B for
Example 1A in Example 5B. .sup.1H NMR (500 MHz, DMSO-D.sub.6)
.delta. ppm 2.14-2.23 (m, 2H) 2.27 (s, 3H) 4.01 (t, J=6.1 Hz, 2H)
4.19 (t, J=6.9 Hz, 2H) 4.31 (s, 2H) 5.97 (t, J=2.2 Hz, 2H) 6.66 (d,
J=7.5 Hz, 1H) 6.71 (d, J=7.8 Hz, 1H) 6.76 (t, J=2.2 Hz, 2H)
6.78-6.81 (m, 1H) 7.10 (dd, J=11.2, 8.4 Hz, 1H) 7.35 (d, J=8.4 Hz,
2H) 7.55 (d, J=8.4 Hz, 2H) 7.99 (dd, J=8.0, 2.0 Hz, 1H) 8.49 (d,
J=2.2 Hz, 1H) 9.14 (s, 1H) 11.90 (s, 1H) MS (ESI(+)) m/e 499.1
(M+H).sup.+.
Example 231
4-(1H-indol-5-yl)-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-3-amine
The desired product was prepared by substituting Example 230B and
indole-5-boronic acid for Example 1A and Example 5A, respectively,
in Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
2.16-2.24 (m, 2H) 4.02 (t, J=6.1 Hz, 2H) 4.21 (t, J=6.6 Hz, 2H)
4.29 (s, 2H) 5.98 (t, J=2.0 Hz, 2H) 6.47-6.49 (m, 1H) 6.67 (d,
J=7.5 Hz, 1H) 6.72 (d, J=7.8 Hz, 1H) 6.78 (t, J=2.0 Hz, 2H) 7.14
(dd, J=8.3, 1.5 Hz, 1H) 7.41 (t, J=2.7 Hz, 1H) 7.49 (d, J=8.1 Hz,
1H) 7.56 (s, 1H) 11.19 (s, 1H) 11.86 (s, 1H) MS (ESI(+)) m/e 372.1
(M+H).sup.+.
Example 232
N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3--
methylphenyl)urea
The desired product was prepared by substituting Example 230B and
N-(3-methylphenyl)N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl]urea for Example 1A and Example 5A, respectively, in Example 5B.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.16-2.24 (m, 2H)
2.29 (s, 3H) 4.02 (t, J=5.9 Hz, 2H) 4.20 (t, J=6.8 Hz, 2H) 5.98 (t,
J=2.2 Hz, 2H) 6.68 (d, J=7.8 Hz, 1H) 6.74 (d, J=7.8 Hz, 1H) 6.77
(t, J=2.0 Hz, 2H) 6.80 (d, J=7.1 Hz, 1H) 7.16 (t, J=7.6 Hz, 1H)
7.25 (d, J=8.1 Hz, 1H) 7.32 (s, 1H) 7.35 (d, J=8.8 Hz, 2H) 7.56 (d,
J=8.8 Hz, 2H) 8.63 (s, 1H) 8.76 (s, 1H) 12.05 (s, 1H) MS (ESI(+))
m/e 481.1 (M+H).sup.+.
Example 233
N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3--
chlorophenyl)urea
The desired product was prepared by substituting Example 230B and
N-(3-chlorophenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
2.15-2.23 (m, 2H) 4.01 (t, J=5.9 Hz, 2H) 4.20 (t, J=6.8 Hz, 2H)
4.33 (s, 2H) 5.98 (t, J=2.2 Hz, 2H) 6.66 (d, J=7.5 Hz, 1H) 6.72 (d,
J=7.8 Hz, 1H) 6.77 (t, J=2.2 Hz, 2H) 7.02 (dt, J=6.4, 2.2 Hz, 1H)
7.28 (m, 2H) 7.36 (d, J=8.5 Hz, 2H) 7.56 (d, J=8.5 Hz, 2H) 732-7.74
(m, 1H) 8.85 (s, 1H) 8.92 (s, 1H) 11.93 (s, 1H) MS (ESI(-)) m/e
499.3 (M-H).sup.-.
Example 234
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)pheny-
l]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide
Example 234A
N-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}thiophene-2-sulfonamide
The desired product was prepared by substituting
2-thiophenesulfonyl chloride for methanesulfonyl chloride in
Example 170B. MS (ESI(+)) m/e 465 (M+H).sup.+.
Example 234B
N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)pheny-
l]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide
The desired product was prepared by substituting Example 234A for
Example 1A in Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.28 (s, 3H) 3.30-3.34 (m, 2H) 4.14 (t, J=5.9 Hz, 2H)
6.68 (d, J=7.5 Hz, 1H) 6.74 (m, J=7.5 Hz, 1H) 6.79-6.83 (m, 1H)
7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.17 (dd, J=5.1, 3.7 Hz, 1H) 7.36 (d,
J=8.8 Hz, 2H) 7.56 (d, J=8.8 Hz, 2H) 7.65 (dd, J=3.7, 1.4 Hz, 1H)
7.92-8.02 (m, 3H) 7.98 (d, J=6.4 Hz, 1H) 8.01 (dd, J=7.8, 2.0 Hz,
1H) 8.51 (d, J=2.4 Hz, 1H) 9.17 (s, 1H) 11.84 (s, 1H) MS (ESI(+))
m/e 580.6 (M+H).sup.+.
Example 235
N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]thiophene-2-sulfonamide
The desired product was prepared by substituting Example 234A and
N-(3-methylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y-
l)phenyl]urea for Example 1A and Example 5A, respectively, in
Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.29
(s, 3H) 3.33 (q, J=5.8 Hz, 2H) 4.14 (t, J=5.8 Hz, 2H) 6.66-6.84 (m,
3H) 7.16 (t, J=7.8 Hz, 1H) 7.17 (dd, J=5.1, 3.7 Hz, 1H) 7.25 (d,
J=8.8 Hz, 1H) 7.31 (s, 1H) 7.35 (d, J=8.5 Hz, 2H) 7.56 (d, J=8.5
Hz, 2H) 7.65 (dd, J=3.7, 1.4 Hz, 1H) 7.93 (dd, J=5.1, 1.4 Hz, 1H)
7.97 (t, J=5.9 Hz, 1H) 8.63 (s, 1H) 8.77 (s, 1H) 11.91 (s, 1H) MS
(ESI(+)) m/e 563.0 (M+H).sup.+.
Example 236
N-(2-{[3-amino-4-(1H-indol-5-yl)-1H-indazol-7-yl]oxy}ethyl)thiophene-2-sul-
fonamide
The desired product was prepared by substituting Example 234A and
indole-5-boronic acid for Example 1A and Example 5A, respectively,
in Example 5B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.33
(q, J=5.4 Hz, 2H) 4.16 (t, J=5.6 Hz, 2H) 6.49-6.49 (m, 1H) 6.74 (d,
J=7.8 Hz, 1H) 6.78 (d, J=7.8 Hz, 1H) 7.15 (dd, J=8.5, 1.7 Hz, 1H)
7.18 (dd, J=4.8, 3.7 Hz, 1H) 7.41 (t, J=2.7 Hz, 1H) 7.49 (d, J=8.1
Hz, 1H) 7.57 (d, J=1.4 Hz, 1H) 7.65 (dd, J=3.7, 1.4 Hz, 1H) 7.94
(dd, J=5.1, 1.4 Hz, 1H) 7.98 (t, J=5.9 Hz, 1H) 11.20 (s, 1H) 11.98
(s, 1 H) MS (ESI(+)) m/e 454.0 (M+H).sup.+.
Example 237
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fl-
uoro-5-methylphenyl)urea
Example 237A
3-[3-(diethylamino)propoxy]-2-fluoro-6-iodobenzonitrile
The desired product was prepared by substituting
3-(diethylamino).sup.-propan-1-ol for 2-(4-morpholinyl)ethanol in
Example 75A.
Example 237B
4-(4-aminophenyl)-7-[3-(diethylamino)propoxy]-1H-indazol-3-amine
The desired product was prepared by substituting Example 237A for
Example 15E in Examples 15F-G. MS (ESI(+)) m/e 354 (M+H).sup.+.
Example 237C
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-fl-
uoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 237B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.25 (t, J=7.3 Hz, 6H)
2.11-2.20 (m, 2H) 2.28 (s, 3H) 3.16-2.35 (m, 4H) 3.31-3.41 (m, 2H)
4.24 (t, J=5.8 Hz, 2H) 6.71 (d, J=7.5 Hz, 1H) 6.79-6.84 (m, 2H)
7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.36 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5
Hz, 2H) 8.00 (dd, J=7.8, 2.0 Hz, 1H) 8.52 (d, J=2.4 Hz, 1H) 9.07
(s, 1H) 9.18 (s, 1H) 11.93 (s, 1H) MS (APCI(+)) ink 505.4
(M+H).sup.+.
Example 238
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-ch-
lorophenyl)urea
The desired product was prepared by substituting Example 237B and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.25 (t, J=7.29 Hz, 6H)
2.11-2.20 (m, 2H) 3.16-3.25 (m, 4H) 3.34-3.14 (m, 2H) 4.24 (t,
J=5.8 Hz, 2H) 6.71 (d, J=7.8 Hz, 1H) 6.81 (d, J=7.8 Hz, 1H) 7.03
(dt, J=6.4, 2.4 Hz, 1H) 7.26-7.32 (m, 2H) 7.36 (d, J=8.8 Hz, 2H)
7.57 (d, J=8.8 Hz, 2H) 7.73-7.74 (m, 1H) 8.92 (s, 1H) 8.98 (s, 1H)
9.05 (s, 1H) 11.92 (s, 1H) MS (ESI(+)) m/e 506.9 (M+H).sup.+.
Example 239
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(t-
rifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 237B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.24 (t, J=7.3 Hz, 6H)
2.11-2.20 (m, 2H) 3.16-3.25 (m, 4H) 3.31-3.37 (m, 2H) 4.24 (t,
J=5.6 Hz, 2H) 6.71 (d, J=7.8 Hz, 1H) 6.81 (m, J=7.8 Hz, 1H) 7.32
(d, J=7.1 Hz, 1H) 7.36 (d, J=8.5 Hz, 2H) 7.50-7.61 (m, 4 H) 8.04
(s, 1H) 8.95 (s, 1H) 9.04 (s, 1H) 9.13 (s, 1H) 11.92 (s, 1H) MS
(ESI(+)) m/e 541.2 (M+H).sup.+.
Example 240
N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-fl-
uorophenyl)urea
The desired product was prepared by substituting Example 237B for
Example 15G in Example 15H. NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
1.25 (t, J=7.3 Hz, 6H) 2.11-2.20 (m, 2H) 3.16-3.24 (m, 4H)
3.34-3.43 (m, 2H) 4.24 (t, J=5.6 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H)
6.76-6.82 (m, 1H) 6.81 (d, J=7.8 Hz, 1H) 7.14 (ddd, J=8.1, 2.0, 0.7
Hz, 1H) 7.28-7.35 (m, 1 H) 7.36 (d, J=8.8 Hz, 2H) 7.52 (dt, J=12.0,
2.3 Hz, 1H) 7.57 (d, J=8.8 Hz, 2H) 8.92 (s, 1H) 9.01 (s, 1H) 9.06
(s, 1H) 11.94 (s, 1H) MS (APCI(-)) m/e 489.3 (M-H).sup.-.
Example 241
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-[3-(trifluoromethyl)phen-
yl]urea
The desired product was prepared by substituting
1-isocyanato-3-(trifluoromethyl)benzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 4.37 (s, 2H) 6.80-6.86 (m, 1H) 7.26-7.35
(m, 4H) 7.39 (dd, J=12.2, 1.7 Hz, 1H) 7.54-7.56 (m, 2H) 8.06 (s,
1H) 8.26 (t, J=8.5 Hz, 1H) 8.76 (d, J=2.4 Hz, 1H) 9.47 (s, 1H)
11.77 (s, 1H) MS (ESI(+)) m/e 430.0 (M+H).sup.+.
Example 242
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-[4-fluoro-3-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for
1-isocyanato-3-methylbenzene in Examples 44A-B. NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 4.37 (s, 2H) 6.83 (dd, J=4.4, 3.7 Hz, 1H)
7.25-7.29 (m, 3H) 7.38 (dd, J=12.0, 1.9 Hz, 1H) 7.46 (t, J=9.8 Hz,
1H) 7.61-7.66 (m, 1H) 8.05 (dd, J=6.4, 2.7 Hz, 1H) 8.23 (t, J=8.5
Hz, 1H) 8.75 (d, J=1.7 Hz, 1H) 9.45 (s, 1H) 11.77 (s, 1H) MS
(ESI(+)) m/e 448.0 (M+H).sup.+.
Example 243
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methyl-
phenyl)urea
Example 243A
3-fluoro-1,1'-biphenyl-2-carbonitrile
The desired product was prepared by substituting
2-fluoro-6-iodobenzonitrile for Example 1A and phenylboronic acid
for Example 1B in Example 1C. Additionally, toluene/EtOH/H2O
(3:2:1) was substituted for DME/H2O as the solvent.
Example 243B
3-fluoro-4-iodo-1,1'-biphenyl-2-carbonitrile
A solution of Example 243A (6.8 g, 34.5 mmol) in THF (110 mL) at
-78.degree. C. under nitrogen atmosphere was treated dropwise with
LDA (2.0 M solution in THF) and stirred for 1 h, then a solution of
iodine in THF (30 mL) was added via cannula over about 10 min. The
thick mixture was allowed to warm to rt and stirred for 1 h, then
treated with saturated aqueous Na2S2O3 solution (10 mL). The
mixture was concentrated to remove the THF, then H2O was added and
the mixture was extracted with EtOAc. The extracts were washed with
brine, dried (MgSO4) and concentrated. The residue was purified by
flash chromatography on silica gel, eluting with EtOAc/hexanes
(1:7), and the resulting solid was triturated with hexanes and
EtOAc to give the desired product (6.8 g). Rf=0.44 (7:1
hexane:EtOAc)
Example 243C
3-fluoro-4-iodo-4'-nitro-1,1'-biphenyl-2-carbonitrile
A solution of Example 243B (2.77 g, 8.6 mmol) in 1,2-dichloroethane
(50 mL) under nitrogen atmosphere was treated with nitronium
tetrafluoroborate (85% technical grade, 2.0 g, 12.9 mmol) and the
mixture was stirred for 3.5 h, at which time an additional portion
of nitronium tetrafluoroborate (700 mg, 5.3 mmol) was added. The
reaction was stirred for another 2 h, then poured over ice, and
once melted the mixture was neutralized with sat. NaHCO3 solution.
The mixture was extracted with EtOAc, and the extracts were washed
with brine, dried (MgSO4) and concentrated. The residue was
purified by flash chromatography on silica gel, eluting with
hexanes/EtOAc (4:1) to give the desired product (1.84 g). MS
(ESI(-)) m/e 367.9 (M-H).sup.-.
Example 243D
3-fluoro-4'-nitro-4-pyridin-3-yl-1,1'-biphenyl-2-carbonitrile
The desired product was prepared by substituting Example 243C and
pyridine-3-boronic acid for Examples 1A and 1B, respectively, in
Example 1C. Additionally, PdCl2(dppf) was used in place of
Pd(PPh3)4. MS (ESI(+)) m/e 320.0 (M+H).sup.+.
Example 243E
4-(4-aminophenyl)-7-pyridin-3-yl-1H-indazol-3-amine
The desired product was prepared by substituting Example 243D for
2-fluoro-6-iodobenzonitrile in Example 1A. In addition to pyrazole
cyclization, nitro reduction was also accomplished in this
reaction. MS (ESI(+)) m/e 302.0 (M+H).sup.+.
Example 243F
N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N'-[4-fluoro-3-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting Example 243E and
1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.23 (d, J=1.7 Hz, 3H) 6.97
(d, J=7.5 Hz, 1H) 7.06 (t, J=9.2 Hz, 1H) 7.29 (ddd, J=8.7, 4.5, 3.1
Hz, 1H) 7.39 (dd, J=6.8, 2.8 Hz, 1H) 7.43-7.47 (m, 3H) 7.62 (d,
J=8.5 Hz, 2H) 7.69-7.80 (m, 1H) 8.32 (d, J=7.8 Hz, 1H) 8.67-8.80
(m, 1H) 8.71 (s, 1H) 8.87 (s, 1H) 8.90-9.15 (m, 1H) 11.81-12.42
(br. s., 1H) MS (ESI(+)) m/e 453.1 (M+H).sup.+.
Example 244
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)ur-
ea
The desired product was prepared by substituting Example 243E and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 6.96 (d, J=7.5 Hz, 1H)
7.02-7.05 (m, 1H) 7.28-7.35 (m, 2H) 7.44-7.47 (m, 3H) 7.63 (d,
J=8.8 Hz, 2H) 7.66-7.72 (m, 1H) 7.74-7.75 (m, 1H) 8.27 (d, J=7.5
Hz, 1H) 8.61-8.85 (m, 1H) 8.93-9.04 (m, 3H) 11.73-12.36 (br. s.,
1H) MS (ESI(+)) m/e 455.1 (M+H).sup.+.
Example 245
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethy-
l)phenyl]urea
The desired product was prepared by substituting Example 243E and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 6.97 (d, J=7.1 Hz, 1H) 7.33
(d, J=7.5 Hz, 1H) 7.44-7.47 (m, 3H) 7.53 (t, J=7.8 Hz, 1H)
7.60-7.70 (m, 4H) 8.05 (s, 1H) 8.26 (d, J=8.1 Hz, 1H) 8.61-8.81 (m,
1H) 8.89-9.08 (m, 2H) 9.15 (s, 1H) 11.79-12.29 (br. s., 1H) MS
(ESI(+)) m/e 489.1 (M+H).sup.+.
Example 246
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methyl-
phenyl)urea
The desired product was prepared by substituting Example 243E and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H) 6.79-6.84 (m,
1H) 6.96 (d, J=7.5 Hz, 1H) 7.12 (dd, J=11.4, 8.3 Hz, 1H) 7.44-7.47
(m, 3H) 7.63 (d, J=8.8 Hz, 2H) 7.65-7.73 (m, 1H) 8.01 (dd, J=8.0,
1.9 Hz, 1H) 8.26 (d, J=7.8 Hz, 1H) 8.55 (d, J=2.4 Hz, 1H) 8.63-8.82
(m, 1H) 8.88-9.11 (m, 1H) 9.24 (s, 1H) 11.79-12.33 (br. s., 1H) MS
(ESI(+)) m/e 453.1 (M+H).sup.+.
Example 247
N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifl-
uoromethyl)phenyl]urea
The desired product was prepared by substituting Example 243E and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 6.95 (d, J=7.5 Hz, 1H)
7.40-7.49 (m, 4H) 7.61-7.70 (m, 4H) 8.04 (dd, J=6.4, 2.7 Hz, 1H)
8.19-8.23 (m, 1H) 8.67 (dd, J=4.8, 1.4 Hz, 1H) 8.94-8.97 (m, 1H)
9.00 (s, 1H) 9.12 (s, 1H) 12.02 (s, 1H) MS (ESI(+)) m/e 507.1
(M+H).sup.+.
Example 248
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-m-
ethylphenyl)urea
Example 248A
3-[3-(dimethylamino)propoxy]-2-fluoro-6-iodobenzonitrile
The desired product was prepared by substituting
3-(dimethylamino).sup.-propan-1-ol for 2-(4-morpholinyl)ethanol in
Example 75A. MS (ESI(+)) m/e 349 (M+H).sup.+.
Example 248B
4-(4-aminophenyl)-7-[3-(dimethylamino)propoxy]-1H-indazol-3-amine
The desired product was prepared by substituting Example 248A for
Example 15E in Examples 15F-G. MS (ESI(+)) m/e 326 (M+H).sup.+.
Example 248C
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-m-
ethylphenyl)urea
The desired product was prepared by substituting Example 248B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13-2.22 (m, 2H) 2.28 (s,
3H) 2.86 (d, J=5.1 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J=5.8 Hz, 2H)
6.72 (d, J=7.8 Hz, 1H) 6.80 (d, J=7.1 Hz, 1H) 6.82 (d, J=7.8 Hz,
1H) 7.16 (t, J=7.8 Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.32 (s, 1H) 7.34
(d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 8.68 (s, 1H) 8.83 (s, 1H)
9.40 (s, 1H) 11.94 (s, 1H) MS (ESI(+)) m/e 459.2 (M+H).sup.+.
Example 249
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(2-f-
luoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 248B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13-2.22 (m, 2H) 2.28 (s,
3H) 2.86 (d, J=4.8 Hz, 6H) 3.34-3.42 (m, 2H) 4.22 (t, J=5.9 Hz, 2H)
6.72 (d, J=7.8 Hz, 1H) 6.79-6.83 (m, 2H) 7.12 (dd, J=11.2, 8.5 Hz,
1H) 7.36 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 8.00 (dd, J=8.0,
1.9 Hz, 1H) 8.53 (d, J=2.4 Hz, 1H) 9.19 (s, 1H) 9.41 (s, 1H) 11.94
(s, 1H) MS (ESI(+)) m/e 477.1 (M+H).sup.+.
Example 250
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-f-
luorophenyl)urea
The desired product was prepared by substituting Example 248B for
Example 15G in Example 15H. NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
2.13-2.22 (m, 2H) 2.86 (d, J=4.8 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t,
J=5.9 Hz, 2H) 6.73 (d, J=7.5 Hz, 1H) 6.79 (td, J=8.6, 2.5 Hz, 1H)
6.83 (d, J=7.8 Hz, 1H) 7.14 (ddd, J=8.1, 2.0, 1.0 Hz, 1H) 7.26-7.37
(m, 1H) 7.36 (d, J=8.5 Hz, 2H) 7.52 (dt, J=12.0, 2.3 Hz, 1H) 7.58
(d, J=8.5 Hz, 2H) 8.98 (s, 1H) 9.07 (s, 1H) 9.44 (s, 1H) 11.99 (s,
1H) MS (ESI(+)) m/e 463.2 (M+H).sup.+.
Example 251
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(3-c-
hlorophenyl)urea
The desired product was prepared by substituting Example 248 and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13-2.22 (m, 2H) 2.86 (d,
J=4.8 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J=5.8 Hz, 2H) 6.73 (d,
J=7.8 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H) 7.03 (ddd, J=6.1, 3.1, 2.4 Hz,
1H) 7.27-7.32 (m, 2H) 7.36 (d, J=8.5 Hz, 2H) 7.58 (d, J=8.5 Hz, 2H)
7.73-7.75 (m, 1H) 8.98 (s, 1H) 9.04 (s, 1H) 9.41 (s, 1H) 11.96 (s,
1H) MS (ESI(+)) m/e 479.1 (M+H).sup.+.
Example 252
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-[3-(-
trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 248B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13-2.22 (m, 2H) 2.86 (d,
J=4.8 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J=5.9 Hz, 2H) 6.72 (d,
J=7.8 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H) 7.32 (d, J=7.5 Hz, 1H) 7.36
(d, J=8.8 Hz, 2H) 7.50-7.61 (m, 4H) 8.05 (s, 1H) 8.98 (s, 1H) 9.16
(s, 1H) 9.38 (s, 1H) 11.92 (s, 1H) MS (ESI(+)) me/513.1
(M+H).sup.+.
Example 253
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-(4-f-
luoro-3-methylphenyl)urea
The desired product was prepared by substituting Example 248B and
1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13-2.19 (m, 2H) 2.22 (d,
J=1.7 Hz, 3H) 2.86 (d, J=5.1 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t,
J=5.9 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H) 6.81 (d, J=7.8 Hz, 1H) 7.05
(t, J=9.2 Hz, 1H) 7.28 (ddd, J=8.8, 4.1, 2.7 Hz, 1H) 7.33-7.39 (m,
3H) 7.56 (d, J=8.5 Hz, 2H) 8.72 (s, 1H) 8.83 (s, 1H) 9.41 (s, 1H)
11.95 (s, 1H) MS (ESI(+)) m/e 477.2 (M+H).sup.+.
Example 254
N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-br-
omophenyl)urea
The desired product was prepared by substituting Example 207B and
1-bromo-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 2.18-2.23 (m, 2H) 3.06-3.19
(m, 4 H) 3.42-3.46 (m, 2H) 3.65-3.70 (m, 2H) 4.00-4.07 (m, 2H) 4.24
(t, J=5.8 Hz, 2H) 6.73 (d, J=7.8 Hz, 1H) 6.83 (d, J=7.8 Hz, 1H)
7.16 (ddd, J=8.1, 1.9, 0.9 Hz, 1H) 7.25 (t, J=8.1 Hz, 1H) 7.32-7.38
(m, 3H) 7.58 (d, J=8.7 Hz, 2H) 7.88 (t, J=1.9 Hz, 1H) 8.99 (s, 1H)
9.04 (s, 1 H) 9.73 (s, 1H) 11.91 (s, 1H) MS (ESI(+)) m/e 565.1,
567.1 (M+H).sup.+.
Example 255
N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(3-methylphenyl)urea
Example 255A
3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
The desired product was prepared by substituting
4-bromo-3-fluoro-phenylamine for Example 149A in Example 149B. The
mixture was heated at 85.degree. C. overnight and the desired
product was purified by flash chromatography using 30% ethyl
acetate in hexanes. MS (ESI(+) m/e 238 (M+H).sup.+.
Example 255B
N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N'-(3-m-
ethylphenyl)urea
The desired product was prepared by substituting Example 255A and
1-isocyanato-3-methylbenzene for 4-bromo-2-ethylaniline and
1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example
149A. MS (ESI(+) m/e 371 (M+H).sup.+.
Example 255C
N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 255B for
Example 1B in Example 1C. .sup.1H NMR (400 MHz, DMSO-D.sub.6)
.delta. ppm 2.29 (s, 3H), 6.81-6.85 (m, 2H), 7.18 (t, J=7.83 Hz,
1H), 7.25 (d, J=1.84 Hz, 1H), 7.27 (d, J=1.84 Hz, 1H), 7.30-7.34
(m, 4H), 7.64 (dd, J=12.73, 1.99 Hz, 1H), 8.74 (s, 1H), 9.04 (s,
1H); MS (ESI(+) m/e 376 (M+H).sup.+.
Example 256
N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
The desired product was prepared by substituting Example 255A for
4-bromo-2-ethylaniline in Example 149A and then substituting the
product for Example 1B in Example 1C. .sup.1H NMR (400 MHz,
DMSO-D.sub.6) .delta. ppm 2.49 (s, 3H), 7.02-7.05 (m, 1H), 7.08 (t,
J=3.84 Hz, 1H), 7.32 (dd, J=11.20, 8.44 Hz, 1H), 7.43-7.45 (m, 1H),
7.52-7.57 (m, 3H), 7.85 (dd, J=12.43, 1.69 Hz, 1H), 8.17 (d, J=7.98
Hz, 1H), 8.80 (d, J=2.15 Hz, 1H), 9.61 (s, 1H); MS (ESI(+) m/e 394
(M+H).sup.+.
Example 257
N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared by substituting Example 255A and
1-chloro-3-isocyanatobenzene for 4-bromo-2-ethylaniline and
1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example
149A and then substituting the product for Example 1B in Example
1C. .sup.1H NMR (400 MHz, DMSO-D.sub.6) .delta. ppm 6.81 (dd,
J=4.91, 2.46 Hz, 1H), 7.03-7.06 (m, 1H), 7.27-7.35 (m, 6H), 7.62
(dd, J=12.43, 1.99 Hz, 1H), 7.72 (t, J=1.99 Hz, 1H), 9.02 (s, 1H),
9.12 (s, 1H); MS (ESI(+) m/e 396 (M+H).sup.+.
Example 258
N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-(4-fluoro-3-methylphenyl-
)urea
The desired product was prepared by substituting Example 255A and
1-fluoro-4-isocyanato-2-methylbenzene for 4-bromo-2-ethylaniline
and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example
149A and then substituting the product for Example 1B in Example
1C. .sup.1H NMR (400 MHz, DMSO-D.sub.6) .delta. ppm 2.22 (s, 3H),
6.87 (t, J=3.84 Hz, 1H), 7.06 (t, J=9.05 Hz, 1H), 7.27-7.38 (m,
6H), 7.63 (dd, J=12.58, 1.53 Hz, 1H), 8.79 (s, 1H), 9.07 (s, 1H);
MS (ESI(+) m/e 394 (M+H).sup.+.
Example 259
N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-[2-fluoro-5-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting Example 255A and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for
4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene,
respectively, in Example 149A and then substituting the product for
Example 1B in Example 1C. .sup.1H NMR (400 MHz, DMSO-D.sub.6)
.delta. ppm 6.89 (t, J=3.84 Hz, 1H), 7.28 (dd, J=8.44, 1.99 Hz,
1H), 7.34-7.38 (m, 3H), 7.42-7.45 (m, 1H), 7.50-7.54 (m, 1H), 7.66
(dd, J=12.43, 1.99 Hz, 1H), 8.61 (dd, J=7.21, 1.99 Hz, 1H), 9.03
(d, J=2.15 Hz, 1H), 9.54 (s, 1H); MS (ESI(+) m/e 448
(M+H).sup.+.
Example 260
N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N'-[4-fluoro-3-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting Example 255A and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for
4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene,
respectively, in Example 149A and then substituting the product for
Example 1B in Example 1C. .sup.1H NMR (400 MHz, DMSO-D.sub.6)
.delta. ppm 6.84 (t, J=3.99 Hz, 1H), 7.29-7.36 (m, 4H), 7.46 (t,
J=9.82 Hz, 1H), 7.62 (dd, J=12.73, 1.69 Hz, 1H), 7.68 (m, 1H), 8.02
(dd, J=6.60, 2.92 Hz, 1H), 9.21 (s, 2H); MS (ESI(+) m/e 448
(M+H).sup.+.
Example 261
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea
Example 261A
4-(4-aminophenyl)-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 95A and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples
1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 226
(M+H).sup.+.
Example 261B
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea
The desired product was prepared by substituting Example 261A and
1-isocyanato-3,5-dimethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 2.24 (s, 6H) 5.22 (s, 2H) 6.63
(s, 1H) 7.10 (s, 2H) 7.14 (d, J=6.8 Hz, 1H) 7.43 (d, J=8.5 Hz, 2H)
7.48 (d, J=8.1 Hz, 1H) 7.56-7.64 (m, 3H) 8.57 (s, 1H) 8.83 (s, 1H)
MS (ESI(+)) m/e 373.1 (M+H).sup.+.
Example 262
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea
The desired product was prepared by substituting Example 261A and
isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene,
respectively, in Example 15H. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 5.22 (s, 2H) 6.99 (t, J=7.5 Hz, 1H) 7.14 (d, J=7.1 Hz,
1H) 7.30 (t, J=8.0 Hz, 2H) 7.44 (d, J=8.5 Hz, 2H) 7.46-7.50 (m, 3H)
7.58 (dd, J=8.3, 7.3 Hz, 1H) 7.63 (d, J=8.5 Hz, 2H) 8.74 (s, 1H)
8.87 (s, 1H) MS (ESI(+)) m/e 345.0 (M+H).sup.+.
Example 263
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)urea
The desired product was prepared by substituting Example 261A and
1-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.25 (s, 3H) 5.22 (s, 2H)
7.10 (d, J=8.5 Hz, 2H) 7.13 (d, J=6.8 Hz, 1H) 7.36 (d, J=8.5 Hz,
2H) 7.43 (d, J=8.5 Hz, 2H) 7.48 (d, J=8.1 Hz, 1H) 7.55-7.63 (m, 3H)
8.62 (s, 1H) 8.83 (s, 1H) MS (ESI(+)) m/e 359.0 (M+H).sup.+.
##STR00013##
Example 264
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-cyanophenyl)urea
The desired product was prepared by substituting Example 261A and
3-isocyanatobenzonitrile for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.22 (s, 2H) 7.14 (dd,
J=7.1, 0.7 Hz, 1H) 7.42-7.50 (m, 4H) 7.51 (t, J=8.0 Hz, 1H) 7.59
(dd, J=8.5, 7.5 Hz, 1H) 7.64 (d, J=8.5 Hz, 2H) 7.71 (ddd, J=8.2,
2.1, 1.2 Hz, 1H) 8.00 (t, J=1.9 Hz, 1H) 9.05 (s, 1H) 9.09 (s, 1H)
MS (ESI(+)) m/e 370.0 (M+H).sup.+.
Example 265
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluoromethy-
l)phenyl]urea
The desired product was prepared by substituting Example 261A and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.22 (s, 2H) 7.14
(d, J=7.1 Hz, 1H) 7.45 (d, J=8.5 Hz, 2H) 7.45 (t, J=9.7 Hz, 1H)
7.49 (dd, J=8.1, 0.7 Hz, 1H) 7.59 (dd, J=8.5, 7.5 Hz, 1H) 7.62-7.70
(m, 3H) 8.03 (dd, J=6.4, 2.7 Hz, 1H) 9.01 (s, 1H) 9.11 (s, 1H) MS
(ESI(+)) mite 431.0 (M+H).sup.+.
Example 266
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
The desired product was prepared by substituting Example 261A and
1-bromo-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.22 (s, 2H) 7.13-7.18 (m,
2H) 7.26 (t, J=8.0 Hz, 1H) 7.34 (ddd, J=8.1, 2.0, 1.4 Hz, 1H) 7.44
(d, J=8.5 Hz, 2H) 7.49 (dd, J=8.5, 0.9 Hz, 1H) 7.59 (dd, J=8.5, 7.1
Hz, 1H) 7.63 (d, J=8.5 Hz, 2H) 7.88 (t, J=1.9 Hz, 1H) 8.95 (s, 1H)
8.96 (s, 1H) MS (ESI(+)) mile 422.9, 424.8 (M+H).sup.+.
Example 267
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N-(3-chlorophenyl)urea
The desired product was prepared by substituting Example 261A and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.75 (s, 2H) 7.03 (dt,
J=6.4, 2.7 Hz, 1H) 7.14 (dd, J=7.1, 0.7 Hz, 1H) 7.28-7.35 (m, 2H)
7.44 (d, J=8.5 Hz, 2H) 7.48 (d, J=8.1 Hz, 1H) 7.59 (dd, J=8.1, 7.5
Hz, 1H) 7.63 (d, J=8.5 Hz, 2H) 7.73 (t, J=2.0 Hz, 1H) 8.96 (app.
s., 2H) MS (ESI(+)) ink 379.0 (M+H).sup.+.
Example 268
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)urea
The desired product was prepared by substituting Example 261A and
3-ethyl-1-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.19 (t, J=7.5 Hz, 3H) 2.59
(q, J=7.5 Hz, 2H) 5.22 (s, 2H) 6.84 (d, J=7.5 Hz, 1H) 7.14 (d,
J=7.1 Hz, 1H) 7.19 (t, J=7.6 Hz, 1H) 7.27 (d, J=7.8 Hz, 1H) 7.34
(s, 1H) 7.43 (d, J=8.5 Hz, 2H) 7.48 (d, J=8.1 Hz, 1H) 7.56-7.64 (m,
3H) 8.67 (s, 1H) 8.84 (s, 1H) MS (ESI(+)) m/e 373.0
(M+H).sup.+.
Example 269
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethyl)phenyl]-
urea
The desired product was prepared by substituting Example 261A and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.22 (s, 2H) 7.15 (d, J=7.1
Hz, 1H) 7.44-7.50 (m, 3H) 7.59 (dd, J=8.5, 7.1 Hz, 1H) 7.63-7.71
(m, 6H) 9.02 (s, 1H) 9.18 (s, 1H) MS (ESI(+)) m/e 413.0
(M+H).sup.+.
Example 270
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-methylphenyl)ur-
ea
The desired product was prepared by substituting Example 261A and
1-fluoro-5-isocyanato-2-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.17 (d, J=1.4 Hz, 3H) 5.22
(s, 2H) 7.05 (dd, J=8.3, 2.2 Hz, 1H) 7.12-7.21 (m, 2H) 7.42-7.50
(m, 4H) 7.56-7.64 (m, 3H) 8.84 (s, 1H) 8.90 (s, 1H) MS (ESI(+)) m/e
377.1 (M+H).sup.+.
Example 271
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)urea
The desired product was prepared by substituting Example 261A for
Example 15G in Example 15H. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 5.22 (s, 2H) 6.77-6.83 (m, 1H) 7.13-7.18 (m, 2H) 7.32
(td, J=8.1, 7.1 Hz, 1H) 7.44 (d, J=8.8 Hz, 2H) 7.48 (dd, J=8.5, 1.0
Hz, 1H) 7.52 (dt, J=11.9, 2.4 Hz, 1H) 7.59 (dd, J=8.1, 7.5 Hz, 1H)
7.63 (d, J=8.8 Hz, 2H) 8.94 (s, 1H) 8.98 (s, 1H) MS (ESI(+)) m/e
363.0 (M+H).sup.+.
Example 272
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-difluorophenyl)urea
The desired product was prepared by substituting Example 261A and
1,3-difluoro-5-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.21 (s, 2H) 6.81 (tt,
J=9.4, 2.3 Hz, 1H) 7.14 (dd, J=7.1, 0.7 Hz, 1H) 7.22 (dd, J=10.0,
2.3 Hz, 2H) 7.45 (d, J=8.5 Hz, 2H) 7.49 (dd, J=8.5, 0.7 Hz, 1H)
7.59 (dd, J=8.5, 7.1 Hz, 1H) 7.63 (d, J=8.5 Hz, 2H) 9.05 (s, 1H)
9.16 (s, 1H) MS (ESI(+)) m/e 381.0 (M+H).sup.+.
Example 273
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)urea
The desired product was prepared by substituting Example 261A and
3-isocyanato-1-methoxybenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.74 (s, 3H) 5.22 (s, 2H)
6.57 (dd, J=8.0, 2.2 Hz, 1H) 6.96 (dd, J=8.1, 1.4 Hz, 1H) 7.14 (d,
J=6.8 Hz, 1H) 7.19 (t, J=8.1 Hz, 1H) 7.21 (t, J=2.2 Hz, 1H) 7.43
(d, J=8.5 Hz, 2H) 7.48 (d, J=7.8 Hz, 1H) 7.58 (dd, J=8.1, 7.1 Hz,
1H) 7.62 (d, J=8.5 Hz, 2H) 8.75 (s, 1H) 8.86 (s, 1H) MS (ESI(+))
m/e 375.1 (M+H).sup.+.
Example 274
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N-(4-methoxyphenyl)urea
The desired product was prepared by substituting Example 261A and
4-isocyanato-1-methoxybenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 3.72 (s, 3H) 5.22 (s, 2H) 6.88
(d, J=8.8 Hz, 2H) 7.13 (dd, J=7.1, 0.7 Hz, 1H) 7.38 (d, J=8.8 Hz,
2H) 7.42 (d, J=8.5 Hz, 2H) 7.48 (dd, J=8.5, 0.7 Hz, 1H) 7.58 (dd,
J=8.5, 7.5 Hz, 1H) 7.62 (d, J=8.5 Hz, 2H) 8.54 (s, 1H) 8.79 (s, 1H)
MS (ESI(+)) ink 375.1 (M+H).sup.+.
Example 275
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]urea
A solution of Example 261A (45 mg, 0.2 mmol) and sodium isocyanate
(26 mg, 0.4 mmol) in HOAc (0.5 mL) and H2O (0.5 mL) was stirred
overnight at rt, then diluted with water. The precipitated solid
was collected by filtration and recrystallized from THF/hexanes to
give an offwhite solid (35 mg, 65%). .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 5.20 (s, 2H) 5.92 (s, 2H) 7.11 (dd,
J=7.3, 0.9 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.46 (dd, J=8.5, 1.0 Hz,
1H) 7.57 (d, J=8.5 Hz, 2H) 7.57 (dd, J=8.1, 7.1 Hz, 1H) 8.72 (s,
1H) MS (ESI(+)) m/e 269.0 (M+H).sup.+.
Example 276
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-nitrophenyl)urea
The desired product was prepared by substituting Example 261A and
1-nitro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.21 (s, 2H) 7.15 (d, J=6.8
Hz, 1H) 7.45-7.50 (m, 3H) 7.57-7.62 (m, 2H) 7.66 (d, J=8.5 Hz, 2H)
7.75 (dd, J=7.8, 1.7 Hz, 1H) 7.84 (dd, J=8.1, 2.4 Hz, 1H) 8.59 (t,
J=2.2 Hz, 1H) 9.09 (s, 1H) 9.34 (s, 1H) MS (ESI(+)) m/e 390.0
(M+H).sup.+.
Example 277
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-fluorophenyl)urea
The desired product was prepared by substituting Example 261A and
1-fluoro-4-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.21 (s, 2H) 7.11-7.17 (m,
3H) 7.40-7.51 (m, 5H) 7.58 (dd, J=8.1, 7.1 Hz, 1H) 7.63 (d, J=8.8
Hz, 2H) 8.80 (s, 1H) 8.90 (s, 1H) MS (ESI(+)) m/e 363.0
(M+H).sup.+.
Example 278
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluorophenyl)urea
The desired product was prepared by substituting Example 261A and
1-fluoro-2-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.22 (s, 2H) 6.99-7.06 (m,
1H) 7.13-7.19 (m, 2H) 7.25 (ddd, J=11.7, 8.1, 1.5 Hz, 1H) 7.45 (d,
J=8.8 Hz, 2H) 7.49 (dd, J=8.5, 1.0 Hz, 1H) 7.59 (dd, J=8.5, 7.5 Hz,
1H) 7.63 (d, J=8.5 Hz, 2H) 8.17 (td, J=8.3, 1.7 Hz, 1H) 8.62 (d,
J=2.4 Hz, 1H) 9.27 (s, 1H) MS (ESI(+)) m/e 363.0 (M+H).sup.+.
Example 279
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-fluorophenyl)ur-
ea
The desired product was prepared by substituting Example 261A and
1-chloro-2-fluoro-5-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.22 (s, 2H) 7.14 (dd,
J=7.3, 0.9 Hz, 1H) 7.34 (m, 2H) 7.44 (d, J=8.5 Hz, 2H) 7.48 (dd,
J=8.3, 0.9 Hz, 1H) 7.58 (dd, J=8.5, 7.1 Hz, 1H) 7.63 (d, J=8.5 Hz,
2H) 7.81-7.84 (m, 1H) 8.95 (s, 1H) 8.97 (s, 1H) MS (ESI(+)) m/e
397.0 (M+H).sup.+.
Example 280
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-methoxyphenyl)u-
rea
The desired product was prepared by substituting Example 261A and
1-chloro-5-isocyanato-2-methoxybenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 3.82 (s, 3H) 5.22 (s, 2H) 7.10
(d, J=9.2 Hz, 1H) 7.14 (dd, J=7.1, 1.0 Hz, 1H) 7.29 (dd, J=9.2, 2.5
Hz, 1H) 7.43 (d, J=8.5 Hz, 2H) 7.48 (dd, J=8.3, 1.0 Hz, 1H) 7.58
(dd, J=8.1, 7.1 Hz, 1H) 7.62 (d, J=8.5 Hz, 2H) 7.68 (d, J=2.5 Hz,
1H) 8.71 (s, 1H) 8.87 (s, 1H) MS (ESI(+)) m/e 409.0
(M+H).sup.+.
Example 281
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(dimethylamino)phenyl]ur-
ea
The desired product was prepared by substituting Example 261A and
4-dimethylamino-1-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.84 (s, 6H) 5.21 (s, 2H)
6.71 (d, J=9.2 Hz, 2H) 7.13 (dd, J=7.1, 1.0 Hz, 1H) 7.28 (d, J=9.2
Hz, 2H) 7.41 (d, J=8.5 Hz, 2H) 7.47 (dd, J=8.5, 1.0 Hz, 1H) 7.58
(dd, J=8.5, 7.1 Hz, 1H) 7.61 (d, J=8.5 Hz, 2H) 8.36 (s, 1 H) 8.73
(s, 1H) MS (ESI(+)) m/e 388.1 (M+H).sup.+.
Example 282
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-1,3-benzodioxol-5-ylurea
The desired product was prepared by substituting Example 261A and
5-isocyanato-benzo[1,3]dioxole for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 5.21 (s, 2H) 5.98 (s, 2H) 6.78
(dd, J=8.5, 2.0 Hz, 1H) 6.84 (d, J=8.5 Hz, 1H) 7.13 (dd, J=7.1, 1.0
Hz, 1H) 7.22 (d, J=2.0 Hz, 1H) 7.42 (d, J=8.5 Hz, 2H) 7.48 (dd,
J=8.1, 1.0 Hz, 1H) 7.58 (dd, J=8.1, 7.5 Hz, 1H) 7.61 (d, J=8.5 Hz,
2H) 8.62 (s, 1H) 8.80 (s, 1H) MS (ESI(+)) m/e 389.0
(M+H).sup.+.
Example 283
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluoromethoxy)phenyl-
]urea
The desired product was prepared by substituting Example 261A and
4-isocyanato-1-(trifluoromethoxy)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.22 (s, 2H) 7.14 (dd,
J=7.1, 1.0 Hz, 1H) 7.30 (d, J=8.8 Hz, 2H) 7.44 (d, J=8.5 Hz, 2H)
7.48 (dd, J=8.5, 0.7 Hz, 1H) 7.59 (dd, J=8.3, 7.3 Hz, 1H) 7.59 (d,
J=8.8 Hz, 2H) 7.63 (d, J=8.5 Hz, 2H) 8.93 (s, 1H) 8.96 (s, 1H) MS
(ESI(-)) m/e 426.9 (M-H).sup.-.
Example 284
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-(trifluoromethoxy)phenyl-
]urea
The desired product was prepared by substituting Example 261A and
2-isocyanato-1-(trifluoromethoxy)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.23 (s, 2H) 7.11 (td,
J=7.6, 2.0 Hz, 1H) 7.15 (d, J=7.1 Hz, 1H) 7.36 (td, J=8.1, 1.4 Hz,
1H) 7.39 (ddd, J=6.6, 3.1, 1.5 Hz, 1H) 7.44-7.50 (m, 3H) 7.59 (dd,
J=8.5, 7.1 Hz, 1H) 7.65 (d, J=8.5 Hz, 2H) 8.28 (dd, J=8.3, 1.5 Hz,
1H) 8.55 (s, 1H) 9.48 (s, 1H) MS (ESI(+)) m/e 429.0
(M+H).sup.+.
Example 285
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoromethyl)ph-
enyl]urea
The desired product was prepared by substituting Example 261A and
1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.22 (s, 2H) 7.15 (dd,
J=7.1, 1.0 Hz, 1H) 7.45-7.51 (m, 3H) 7.59 (dd, J=8.5, 7.1 Hz, 1H)
7.65-7.69 (m, 3H) 8.16 (s, 2H) 9.20 (s, 1H) 9.47 (s, 1H) MS
(ESI(+)) m/e 481.0 (M+H).sup.+.
Example 286
N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chloro-4-methylphenyl)ur-
ea
The desired product was prepared by substituting Example 261A and
1-chloro-5-isocyanato-2-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.27 (s, 3H) 5.22 (s, 2H)
7.14 (dd, J=7.1, 1.0 Hz, 1H) 7.21 (dd, J=8.5, 2.0 Hz, 1H) 7.26 (d,
J=8.5 Hz, 1H) 7.44 (d, J=8.8 Hz, 2 H) 7.48 (dd, J=8.5, 0.7 Hz, 1H)
7.58 (dd, J=8.5, 7.5 Hz, 1H) 7.63 (d, J=8.8 Hz, 2H) 7.71 (d, J=2.0
Hz, 1H) 8.84 (s, 1H) 8.91 (s, 1H) MS (ESI(+)) m/e 393.1
(M+H).sup.+.
Example 287
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluor-
omethyl)phenyl]urea
The desired product was prepared by substituting Example 100C and
1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.97 (s, 3H) 5.21 (s, 2H)
7.06 (d, J=8.1 Hz, 1H) 7.17 (d, J=8.1 Hz, 1H) 7.41 (d, J=8.5 Hz,
2H) 7.63 (d, J=8.5 Hz, 2H) 7.66 (s, 1H) 8.16 (s, 2H) 9.16 (s, 1H)
9.45 (s, 1H) MS (ESI(+)) m/e 511.0 (M+H).sup.+.
Example 288
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluorometh-
oxy)phenyl]urea
The desired product was prepared by substituting Example 100C and
4-isocyanato-1-(trifluoromethoxy)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.96 (s, 3H) 5.20 (s, 2H)
7.04 (d, J=8.1 Hz, 1H) 7.16 (d, J=8.1 Hz, 1H) 7.30 (d, J=8.8 Hz,
2H) 7.39 (d, J=8.5 Hz, 2H) 7.58 (d, J=8.8 Hz, 2H) 7.60 (d, J=8.5
Hz, 2H) 8.89 (s, 1H) 8.94 (s, 1H) MS (ESI(+)) m/e 459.0
(M+H).sup.+.
Example 289
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)u-
rea
The desired product was prepared by substituting Example 100C for
Example 15G in Example 15H. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 3.96 (s, 3H) 5.21 (s, 2H) 6.80 (td, J=8.5, 2.4 Hz, 1H)
7.05 (d, J=7.8 Hz, 1H) 7.12-7.18 (m, 2H) 7.28-7.36 (m, 1H) 7.39 (d,
J=8.5 Hz, 2H) 7.51 (dt, J=11.9, 2.2 Hz, 1H) 7.60 (d, J=8.5 Hz, 2H)
8.91 (s, 1H) 8.96 (s, 1 H) MS (ESI(+)) m/e 393.0 (M+H).sup.+.
Example 290
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)-
urea
The desired product was prepared by substituting Example 100C and
3-isocyanato-1-methoxybenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.74 (s, 3H) 3.96 (s, 3H)
5.21 (s, 2 H) 6.57 (dd, J=8.3, 2.5 Hz, 1H) 6.95 (dd, J=7.8, 1.5 Hz,
1H) 7.04 (d, J=7.8 Hz, 1H) 7.15-7.22 (m, 3H) 7.38 (d, J=8.5 Hz, 2H)
7.59 (d, J=8.5 Hz, 2H) 8.73 (s, 1H) 8.82 (s, 1H) MS (ESI(+)) m/e
405.0 (M+H).sup.+.
Example 291
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-difluorophen-
yl)urea
The desired product was prepared by substituting Example 100C and
1,3-difluoro-5-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.96 (s, 3H) 5.20 (s, 2H)
6.80 (tt, J=9.3, 2.4 Hz, 1H) 7.05 (d, J=8.1 Hz, 1H) 7.17 (d, J=8.1
Hz, 1H) 7.19-7.26 (m, 2H) 7.40 (d, J=8.5 Hz, 2H) 7.60 (d, J=8.5 Hz,
2H) 9.01 (s, 1H) 9.14 (s, 1H) MS (ESI(+)) m/e 411.1
(M+H).sup.+.
Example 292
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)u-
rea
The desired product was prepared by substituting Example 100C and
1-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.25 (s, 3H) 3.96 (s, 3H)
5.20 (s, 2H) 7.04 (d, J=8.1 Hz, 1H) 7.09 (d, J=8.1 Hz, 2H) 7.16 (d,
J=8.1 Hz, 1H) 7.35 (d, J=8.1 Hz, 2H) 7.37 (d, J=8.5 Hz, 2H) 7.58
(d, J=8.5 Hz, 2H) 8.60 (s, 1H) 8.78 (s, 1H) MS (ESI(+)) m/e 389.1
(M+H).sup.+.
Example 293
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)ur-
ea
The desired product was prepared by substituting Example 100C and
1-bromo-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.96 (s, 3H) 5.20 (s, 2H)
7.05 (d, J=7.8 Hz, 1H) 7.14-7.18 (m, 2H) 7.25 (t, J=8.0 Hz, 1H)
7.33 (ddd, J=8.0, 2.0, 1.2 Hz, 1H) 7.39 (d, J=8.5 Hz, 2H) 7.60 (d,
J=8.5 Hz, 2H) 7.88 (t, J=1.9 Hz, 1H) 8.91 (s, 1H) 8.92 (s, 1 H) MS
(ESI(+)) m/e 451.0, 453.0 (M+H).sup.+.
Example 294
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylphen-
yl)urea
The desired product was prepared by substituting Example 100C and
1-isocyanato-3,5-dimethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.24 (s, 6H) 3.96 (s, 3H)
5.20 (s, 2 H) 6.63 (s, 1H) 7.04 (d, J=8.1 Hz, 1H) 7.09 (s, 2H) 7.16
(d, J=8.1 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.59 (d, J=8.5 Hz, 2H)
8.55 (s, 1H) 8.79 (s, 1H) MS (ESI(+)) m/e 403.1 (M+H).sup.+.
Example 295
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(dimethylamino-
)phenyl]urea
The desired product was prepared by substituting Example 100C and
4-dimethylamino-1-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.84 (s, 6H) 3.96 (s, 3H)
5.20 (s, 2 H) 6.71 (d, J=9.2 Hz, 2H) 7.03 (d, J=8.1 Hz, 1H) 7.16
(d, J=8.1 Hz, 1H) 7.28 (d, J=9.2 Hz, 2H) 7.35 (d, J=8.5 Hz, 2H)
7.57 (d, J=8.5 Hz, 2H) 8.35 (s, 1H) 8.68 (s, 1H) MS (ESI(+)) m/e
418.1 (M+H).sup.+.
Example 296
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-1,3-benzodioxol-5-
-ylurea
The desired product was prepared by substituting Example 100C and
5-isocyanato-benzo[1,3]dioxole for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.96 (s, 3H) 5.20 (s, 2H)
5.97 (s, 2 H) 6.78 (dd, J=8.5, 2.0 Hz, 1H) 6.84 (d, J=8.5 Hz, 1H)
7.04 (d, J=8.1 Hz, 1H) 7.16 (d, J=8.1 Hz, 1H) 7.22 (d, J=2.0 Hz,
1H) 7.37 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 8.60 (s, 1H) 8.76
(s, 1H) MS (ESI(+)) m/e 419.1 (M+H).sup.+.
Example 297
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)ur-
ea
Example 297A
4-iodo-7-methyl-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 15C for
2-bromo-6-fluorobenzonitrile in Example 95A. MS (ESI(+)) m/e 274.8
(M+H).sup.+.
Example 297B
4-(4-aminophenyl)-7-methyl-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 297A and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples
1A and 1B, respectively, in Example 1C. MS (ESI(+)) m/e 240.0
(M+H).sup.+.
Example 297C
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)ur-
ea
The desired product was prepared by substituting Example 297B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H) 2.45 (s, 3H)
5.20 (s, 2 H) 6.80 (d, J=7.5 Hz, 1H) 7.03 (d, J=7.1 Hz, 1H) 7.17
(t, J=7.8 Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.31 (s, 1H) 7.38 (dd,
J=7.5, 1.0 Hz, 1H) 7.40 (d, J=8.5 Hz, 2H) 7.61 (d, J=8.5 Hz, 2H)
8.64 (s, 1H) 8.83 (s, 1H) MS (ESI(+)) m/e 373.1 (M+H).sup.+.
Example 298
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)ur-
ea
The desired product was prepared by substituting Example 297B and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.45 (s, 3H) 5.20 (s, 2H)
7.02-7.05 (m, 2H) 7.27-7.32 (m, 2H) 7.37-7.44 (m, 3H) 7.62 (d,
J=8.8 Hz, 2H) 7.73-7.74 (m, 1H) 8.94 (s, 1H) 8.95 (s, 1H) MS
(ESI(+)) m/e 393.0 (M+H).sup.+.
Example 299
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methyl-
phenyl)urea
The desired product was prepared by substituting Example 297B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.28 (s, 3H) 2.45 (s, 3H)
5.20 (s, 2 H) 6.79-6.84 (m, 1H) 7.04 (d, J=7.1 Hz, 1H) 7.11 (dd,
J=11.4, 8.3 Hz, 1H) 7.37-7.43 (m, 3H) 7.61 (d, J=8.5 Hz, 2H) 8.00
(dd, J=7.6, 1.9 Hz, 1H) 8.54 (d, J=2.4 Hz, 1H) 9.24 (s, 1H) MS
(ESI(+)) m/e 391.1 (M+H).sup.+.
Example 300
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifl-
uoromethyl)phenyl]urea
The desired product was prepared by substituting Example 297B and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.46 (s, 3H) 5.20
(s, 2H) 7.05 (d, J=7.5 Hz, 1H) 7.38-7.45 (m, 4H) 7.48-7.55 (m, 1H)
7.63 (d, J=8.5 Hz, 2H) 8.64 (dd, J=7.3, 2.2 Hz, 1H) 8.97 (s, 1H)
9.37 (s, 1H) MS (ESI(+)) m/e 445.0 (M+H).sup.+.
Example 301
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethy-
l)phenyl]urea
The desired product was prepared by substituting Example 297B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.45 (s, 3H) 5.20 (s, 2H)
7.04 (d, J=7.1 Hz, 1H) 7.32 (d, J=7.8 Hz, 1H) 7.38 (dd, J=7.3, 0.9
Hz, 1H) 7.42 (d, J=8.5 Hz, 2H) 7.53 (t, J=8.0 Hz, 1H) 7.59-7.64 (m,
3H) 8.04 (s, 1H) 9.00 (s, 1H) 9.13 (s, 1H) MS (ESI(+)) m/e 427.0
(M+H).sup.+.
Example 302
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3,5-dimethylpheny-
l)urea
The desired product was prepared by substituting Example 297B and
1-isocyanato-3,5-dimethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.24 (s, 6H) 2.45 (s, 3H)
5.20 (s, 2 H) 6.63 (s, 1H) 7.04 (d, J=7.5 Hz, 1H) 7.09 (s, 2H) 7.38
(dd, J=7.3, 0.9 Hz, 1H) 7.40 (d, J=8.5 Hz, 2H) 7.60 (d, J=8.5 Hz,
2H) 8.56 (s, 1H) 8.81 (s, 1H) MS (ESI(+)) m/e 387.1
(M+H).sup.+.
Example 303
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-ethylphenyl)ure-
a
The desired product was prepared by substituting Example 297B and
3-ethyl-1-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.19 (t, J=7.5 Hz, 3H) 2.45
(s, 3H) 2.58 (q, J=7.6 Hz, 2H) 5.20 (s, 2H) 6.84 (d, J=7.5 Hz, 1H)
7.04 (d, J=7.5 Hz, 1H) 7.19 (t, J=7.8 Hz, 1H) 7.27 (ddd, J=8.1,
2.0, 1.4 Hz, 1H) 7.33-7.35 (m, 1H) 7.38 (dd, J=7.3, 0.9 Hz, 1H)
7.40 (d, J=8.5 Hz, 2H) 7.61 (d, J=8.5 Hz, 2H) 8.66 (s, 1H) 8.82 (s,
1H) MS (ESI(+)) m/e 387.1 (M+H).sup.+.
Example 304
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(4-methylphenyl)ur-
ea
The desired product was prepared by substituting Example 297B and
1-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.25 (s, 3H) 2.45 (s, 3H)
5.19 (s, 2 H) 7.03 (d, J=7.5 Hz, 1H) 7.10 (d, J=8.5 Hz, 2H)
7.34-7.41 (m, 5H) 7.60 (d, J=8.5 Hz, 2H) 8.61 (s, 1H) 8.80 (s, 1H)
MS (ESI(+)) m/e 373.1 (M+H).sup.+.
Example 305
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-(trifluorometho-
xy)phenyl]urea
The desired product was prepared by substituting Example 297B and
1-trifluoromethoxy-4-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.45 (s, 3H) 5.20 (s, 2H)
7.04 (d, J=7.5 Hz, 1H) 7.30 (d, J=8.5 Hz, 2H) 7.37-7.42 (m, 3H)
7.57-7.63 (m, 4H) 8.91 (s, 1H) 8.95 (s, 1H) MS (ESI(+)) m/e 443.0
(M+H).sup.+.
Example 306
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluoro-4-methyl-
phenyl)urea
The desired product was prepared by substituting Example 297B and
1-fluoro-5-isocyanato-2-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.17 (s, 3H) 2.45 (s, 3H)
5.20 (s, 2 H) 7.04 (d, J=7.5 Hz, 1H) 7.05 (dd, J=8.1, 2.0 Hz, 1H)
7.18 (t, J=8.7 Hz, 1H) 7.37-7.39 (m, 1H) 7.41 (d, J=8.5 Hz, 2H)
7.46 (dd, J=12.6, 2.0 Hz, 1H) 7.60 (d, J=8.5 Hz, 2H) 8.84 (s, 1 H)
8.88 (s, 1H) MS (ESI(+)) m/e 391.1 (M+H).sup.+.
Example 307
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methoxyphenyl)u-
rea
The desired product was prepared by substituting Example 297B and
1-methoxy-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.45 (s, 3H) 3.74 (s, 3H)
5.20 (s, 2 H) 6.57 (dd, J=8.1, 2.4 Hz, 1H) 6.95 (dd, J=7.6, 1.5 Hz,
1H) 7.04 (d, J=7.5 Hz, 1H) 7.16-7.22 (m, 2H) 7.37-7.43 (m, 3H) 7.61
(d, J=8.5 Hz, 2H) 8.74 (s, 1H) 8.84 (s, 1H) MS (ESI(+)) m/e 389.0
(M+H).sup.+.
Example 308
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-phenylurea
The desired product was prepared by substituting Example 297B and
isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene,
respectively, in Example 15H. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.45 (s, 3H) 5.20 (s, 2H) 6.98 (tt, J=7.1, 1.4 Hz, 1H)
7.04 (d, J=7.5 Hz, 1H) 7.27-7.32 (m, 2H) 7.38 (dd, J=7.5, 1.0 Hz,
1H) 7.40 (d, J=8.8 Hz, 2H) 7.48 (dd, J=8.8, 1.0 Hz, 2H) 7.61 (d,
J=8.8 Hz, 2H) 8.72 (s, 1H) 8.85 (s, 1H) MS (ESI(+)) m/e 359.0
(M+H).sup.+.
Example 309
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-[3,5-bis(trifluoro-
methyl)phenyl]urea
The desired product was prepared by substituting Example 297B and
1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.45 (s, 3H) 5.20 (s, 2H)
7.05 (d, J=7.1 Hz, 1H) 7.39 (dd, J=7.5, 0.7 Hz, 1H) 7.43 (d, J=8.5
Hz, 2H) 7.63-7.66 (m, 3H) 8.16 (s, 2H) 9.18 (s, 1H) 9.45 (s, 1H) MS
(ESI(+)) m/e 495.0 (M+H).sup.+.
Example 310
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-bromophenyl)ure-
a
The desired product was prepared by substituting Example 297B and
1-bromo-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.45 (s, 3H) 5.20 (s, 2H)
7.04 (d, J=7.1 Hz, 1H) 7.16 (ddd, J=7.8, 1.9, 1.2 Hz, 1H) 7.25 (t,
J=8.0 Hz, 1H) 7.33 (ddd, J=8.0, 2.0, 1.2 Hz, 1H) 7.38 (m, J=7.5,
1.0 Hz, 1H) 7.41 (d, J=8.5 Hz, 2H) 7.61 (d, J=8.5 Hz, 2H) 7.88 (t,
J=1.9 Hz, 1H) 8.93 (app. s., 2H) MS (ESI(+)) ink 436.9, 438.9
(M+H).sup.+.
Example 311
N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-fluorophenyl)ur-
ea
The desired product was prepared by substituting Example 297B for
Example 15G in Example 15H. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.45 (s, 3H) 5.19 (s, 2H) 6.80 (tdd, J=8.5, 2.7, 1.0
Hz, 1H) 7.04 (d, J=7.5 Hz, 1H) 7.14 (ddd, J=8.2, 2.0, 0.7 Hz, 1H)
7.32 (td, J=8.2, 7.0 Hz, 1H) 7.37-7.44 (m, 3H) 7.51 (dt, J=12.0,
2.3 Hz, 1H) 7.61 (d, J=8.5 Hz, 2H) 8.92 (s, 1H) 8.96 (s, 1H) MS
(ESI(+)) m/e 377.1 (M+H).sup.+.
Example 312
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-(trif-
luoromethyl)phenyl]urea
The desired product was prepared by substituting Example 100C and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.96 (s, 3H) 5.20
(s, 2H) 7.05 (d, J=8.1 Hz, 1H) 7.16 (d, J=8.1 Hz, 1H) 7.39 (d,
J=8.5 Hz, 2H) 7.45 (t, J=9.8 Hz, 1H) 7.61 (d, J=8.5 Hz, 2H)
7.64-7.69 (m, 1H) 8.02 (dd, J=6.4, 2.7 Hz, 1H) 8.97 (s, 1H) 9.09
(s, 1H) MS (ESI(+)) m/e 461.0 (M+H).sup.+.
Example 313
N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N-(4-fluoro-3-methyl-
phenyl)urea
The desired product was prepared by substituting Example 100C and
1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.22 (d, J=2.0 Hz, 3H) 3.96
(s, 3H) 5.20 (s, 2H) 7.03-7.09 (m, 2H) 7.16 (d, J=8.1 Hz, 1H) 7.27
(ddd, J=8.5, 4.1, 3.0 Hz, 1H) 7.35-7.39 (m, 3H) 7.59 (d, J=8.5 Hz,
2H) 8.66 (s, 1H) 8.81 (s, 1H) MS (ESI(+)) m/e 407.1
(M+H).sup.+.
Example 314
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[3-(trifluoromethy-
l)phenyl]urea
Example 314A
7-fluoro-4-iodo-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 26A for
2-bromo-6-fluorobenzonitrile in Example 95A. MS (ESI(+)) m/e 278.8
(M+H).sup.+.
Example 314B
4-(4-aminophenyl)-7-fluoro-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 314A and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples
1A and 1B, respectively, in Example 1C. MS (ESI(+)) ink 244.0
(M+H).sup.+.
Example 314C
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N-[3-(trifluoromethyl-
)phenyl]urea
The desired product was prepared by substituting Example 314B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.38 (s, 2H) 7.12 (dd,
J=8.3, 3.9 Hz, 1H) 7.33 (d, J=7.8 Hz, 1H) 7.43 (d, J=8.8 Hz, 2H)
7.52 (dd, J=10.9, 8.1 Hz, 1H) 7.53 (t, J=7.8 Hz, 1H) 7.59-7.65 (m,
3H) 8.04 (s, 1H) 9.00 (s, 1H) 9.12 (s, 1H) MS (ESI(+)) m/e 431.0
(M+H).sup.+.
Example 315
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-chlorophenyl)ur-
ea
The desired product was prepared by substituting Example 314B and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.38 (s, 2H) 7.03 (dt,
J=6.4, 2.2 Hz, 1H) 7.12 (dd, J=8.1, 4.1 Hz, 1H) 7.27-7.35 (m, 2H)
7.42 (d, J=8.5 Hz, 2H) 7.52 (dd, J=10.9, 8.1 Hz, 1H) 7.62 (d, J=8.5
Hz, 2H) 7.72-7.74 (m, 1H) 8.95 (s, 1H) 8.96 (s, 1H) MS (ESI(+)) m/e
397.0 (M+H).sup.+.
Example 316
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifl-
uoromethyl)phenyl]urea
The desired product was prepared by substituting Example 314B and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.37 (s, 2H) 7.12
(dd, J=8.1, 4.1 Hz, 1H) 7.43 (d, J=8.5 Hz, 2H) 7.43 (d, J=9.2 Hz,
1H) 7.52 (dd, J=10.9, 8.1 Hz, 1H) 7.63 (d, J=8.5 Hz, 2H) 7.64-7.69
(m, 1H) 8.02 (dd, J=6.4, 2.7 Hz, 1H) 9.01 (s, 1H) 9.10 (s, 1H) MS
(ESI(+)) m/e 449.0 (M+H).sup.+.
Example 317
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(3-methylphenyl)ur-
ea
The desired product was prepared by substituting Example 314B and
1-isocyanato-3-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H) 5.38 (s, 2H)
6.81 (d, J=7.5 Hz, 1H) 7.11 (dd, J=8.1, 4.1 Hz, 1H) 7.17 (t, J=7.8
Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.32 (s, 1H) 7.41 (d, J=8.5 Hz, 2H)
7.51 (dd, J=10.9, 8.1 Hz, 1H) 7.62 (d, J=8.5 Hz, 2H) 8.65 (s, 1H)
8.85 (s, 1H) MS (ESI(+)) m/e 377.1 (M+H).sup.+.
Example 318
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifl-
uoromethyl)phenyl]urea
The desired product was prepared by substituting Example 314B and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.38 (s, 2H) 7.12
(dd, J=8.3, 3.9 Hz, 1H) 7.38-7.55 (m, 5H) 7.64 (d, J=8.8 Hz, 2H)
8.64 (dd, J=7.3, 2.2 Hz, 1H) 8.97 (d, J=3.1 Hz, 1H) 9.37 (s, 1H) MS
(ESI(+)) m/e 449.0 (M+H).sup.+.
Example 319
N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N'-(2-fluoro-5-methyl-
phenyl)urea
The desired product was prepared by substituting Example 314B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.28 (s, 3H) 5.38 (s, 2H)
6.79-6.84 (m, 1H) 7.08-7.15 (m, 2H) 7.43 (d, J=8.5 Hz, 2H) 7.52
(dd, J=10.9, 8.1 Hz, 1H) 7.62 (d, J=8.5 Hz, 2H) 8.00 (dd, J=7.6,
1.9 Hz, 1H) 8.55 (d, J=2.4 Hz, 1H) 9.25 (s, 1H) MS (ESI(+)) m/e
395.0 (M+H).sup.+.
Example 320
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-flu-
oro-5-(trifluoromethyl)phenyl]urea
Example 320A
6-bromo-2-fluoro-3-(trifluoromethoxy)benzonitrile
The desired product was prepared by substituting
4-bromo-2-fluoro-1-trifluoromethoxy-benzene for
2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C. MS (ESI(-)) m/e
282 (M-H).sup.-.
Example 320B
4-bromo-7-(trifluoromethoxy)-1,2-benzisoxazol-3-amine
A solution of propan-2-one oxime (810 mg, 1.1 mmol) in THF (50 mL)
was treated with potassium tert-butoxide (1.23 g) stirred at r.t
for 30 min, then treated with example 320A (2.84 g, 10 mmol). The
reaction mixture was stirred at r.t. for 30 min, then partitioned
between EtOAc and water. The organic extract was washed with brine,
dried (MgSO4) and concentrated. The residue was dissolved in
ethanol (20 mL), treated with 5% HCl (20 mL) and heated at reflux
for 2 h. The reaction was allowed to cool to r.t the concentrated
to half its volume resulting in a precipitate which was collected
via filtration. The crude solid was purified via silica gel
chromatography eluting with 0 to 10% EtOAc-hexanes to give 0.95 g
of example 320B. MS (ESI(+)) m/e 297, 299 (M+H).sup.+.
Example 320C
4-(4-aminophenyl)-7-(trifluoromethoxy)-1,2-benzisoxazol-3-amine
The desired product was prepared by substituting Example 320B for
Example 15H in Example 15G. MS (ESI(+)) m/e 310 (M+H).sup.+.
Example 320D
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[2-flu-
oro-5-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 320C and
1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.44 (s, 2H), 7.22
(d, J=7.80 Hz, 1H), 7.35-7.46 (m, 1H), 7.46-7.52 (m, 3H), 7.62-7.72
(m, 3H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.98 (d, J=2.71 Hz, 1H),
9.40 (s, 1H); MS (ESI(+)) m/e 515 (M+H).sup.+.
Example 321
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[3-(tr-
ifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 320C and
1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.44 (s, 2H), 7.22 (d,
J=8.14 Hz, 1H), 7.33 (d, J=7.80 Hz, 1H), 7.45-7.72 (m, 7H), 8.04
(s, 1H), 9.03 (s, 1H), 9.13 (s, 1H); MS (ESI(+)) m/e 497
(M+H).sup.+.
Example 322
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(2-flu-
oro-5-methylphenyl)urea
The desired product was prepared by substituting Example 320C and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.28 (s, 3H), 5.44 (s, 2H),
6.75-6.90 (m, 1H), 7.12 (dd, J=11.36, 8.31 Hz, 1H), 7.21 (d, J=8.14
Hz, 1H), 7.47 (d, J=8.82 Hz, 2H), 7.55-7.75 (m, 3H), 8.00 (dd,
J=7.97, 1.86 Hz, 1H), 8.56 (d, J=2.71 Hz, 1H), 9.28 (s, 1H); MS
(ESI(+)) m/e 461 (M+H).sup.+.
Example 323
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-chl-
orophenyl)urea
The desired product was prepared by substituting Example 320C and
3-chloro-1-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.43 (s, 2H), 7.95-7.06 (m,
1H), 7.21 (d, J=8.14 Hz, 1H), 7.25-7.35 (m, 2H), 7.47 (d, J=8.48
Hz, 2H), 7.6-7.9 (m, 4H), 8.97 (s, 1H), 8.99 (s, 1H); MS (ESI(+))
m/e 463 (M+H).sup.+.
Example 324
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(3-bro-
mophenyl)urea
The desired product was prepared by substituting Example 320C and
3-bromo-1-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.43 (s, 2H), 7.10-7.37 (m,
4H), 7.47 (d, J=8.82 Hz, 2H), 7.60-7.72 (m, 3H), 7.88 (t, J=2.03
Hz, 1H), 8.96 (s, 1H), 8.99 (s, 1H); MS (ESI(+)) m/e 507
(M+H).sup.+.
Example 325
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-[4-flu-
oro-3-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 320C and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 5.43 (s, 2H), 7.21
(d, J=8.14 Hz, 1H), 7.40-7.52 (m, J=9.15, 9.15 Hz, 3H), 7.60-7.75
(m, 4H), 7.90-8.10 (dd, J=6.44, 2.71 Hz, 1H), 9.04 (s, 1H), 9.12
(s, 1H); MS (ESI(+)) m/e 515 (M+H).sup.+.
Example 326
N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N'-(4-flu-
oro-3-methylphenyl)urea
The desired product was prepared by substituting Example 320C and
1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.23 (s, 3H), 5.43 (s, 2H),
7.06 (t, J=9.16 Hz, 1H), 7.21 (d, J=8.14 Hz, 1H), 7.25-7.40 (m,
2H), 7.45 (d, J=8.48 Hz, 2H), 7.58-7.78 (m, 3H), 8.69 (s, 1H), 8.88
(s, 1H); MS (ESI(+)) m/e 461 (M+H).sup.+.
Example 327
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea
Example 327A
2-(benzylthio)-6-iodobenzonitrile
A suspension of potassium tert-butoxide (1.12 g, 10.0 mmol) and
phenyl-methanethiol (1.24 g, 10 mmol) in THF (30 mL) at room
temperature was stirred for 10 minutes before treating with
2-fluoro-6-iodo-benzonitrile (2.47 g, 10 mmol). The solution was
stirred for 1 hour at room temperature, poured into a saturated
ammonium chloride solution and filtered. The filter cake was
recrystallized from hexanes to provide 2.41 g (53% yield) of the
desired product. MS (ESI(-)) m/e 350.0 (M-H).sup.-.
Example 327B
4-iodo-1,2-benzisothiazol-3-amine
Example 327A (2.5 g, 7.1 mmol) was treated with sulfuryl chloride
(1.0 M in dichloromethane, 3.5 mL, 35.5 mmol), stirred at room
temperature for 2 hours and concentrated. The residue was dissolved
in minimal THF, treated with ammonia (7.0 M in methanol, 10 mL),
stirred at room temperature for 1 hour, diluted with water and
extracted with ethyl acetate. The combine organic layers were
washed with brine, dried (MgSO.sub.4), filtered and concentrated.
The residue was triturated from ethyl acetate/hexanes to provide
1.2 g (61% yield) of the desired product. MS (ESI(-)) m/e 274.8,
276.7 (M-H).sup.-.
Example 327C
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3,5-dimethylphenyl)urea
The desired product was prepared by substituting
1-isocyanato-3,5-dimethylbenzene for 1-isocyanato-3-methylbenzene,
in example 1B and Example 327B for example 1A in example 1C. In
addition PdCl.sub.2.dppf.CH.sub.2Cl.sub.2 was used in place of
Pd(PPh.sub.3).sub.4. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta.
ppm 2.24 (s, 6H), 5.45 (s, 2H), 6.63 (s, 1H), 7.09 (s, 2H), 7.35
(d, J=8.48 Hz, 2H), 7.50-7.70 (m, 3H), 7.97 (d, J=8.14 Hz, 1H),
8.59 (s, 1H), 8.85 (s, 2H); MS (ESI(F)) m/e 389.0 (M+H).sup.+.
Example 328
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared by substituting
3-chloro-1-isocyanatobenzene for 1-isocyanato-3-methylbenzene, in
example 1B and Example 327B for example 1A in example 1C. In
addition PdCl.sub.2.dppf.CH.sub.2Cl.sub.2 was used in place of
Pd(PPh.sub.3).sub.4. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta.
ppm 5.45 (s, 2H), 7.01-7.10 (m, 1H), 7.17 (d, J=7.80 Hz, 1H),
7.30-7.40 (m, 3H), 7.50-7.65 (m, 4H), 7.70-7.80 (m, 1H), 7.97 (dd,
J=7.97, 0.85 Hz, 1H), 9.00 (s, 2H); MS (ESI(+)) m/e 395.0
(M+H).sup.+.
Example 329
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)-
urea
The desired product was prepared by substituting
1-fluoro-2-isocyanato-4-methylbenzen for
1-isocyanato-3-methylbenzene, in example 1B and Example 327B for
example 1A in example 1C. In addition
PdCl.sub.2.dppf.CH.sub.2Cl.sub.2 was used in place of
Pd(PPh.sub.3).sub.4. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta.
ppm 2.28 (s, 3H), 5.45 (s, 2H) 6.78-6.88 (m, 1H) 7.05-7.25 (m, 2H),
7.37 (d, J=8.48 Hz, 2H), 7.50-7.70 (m, 3H), 7.90-8.10 (m, 2H), 8.56
(d, J=2.37 Hz, 1H), 9.28 (s, 1H); MS (ESI(+)) m/e 393.0
(M+H).sup.+.
Example 330
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 327B for
example 1A in example 1C. In addition
PdCl.sub.2.dppf.CH.sub.2Cl.sub.2 was used in place of
Pd(PPh.sub.3).sub.4. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta.
ppm 2.29 (s, 3H), 5.45 (s, 2H), 6.81 (d, J=7.46 Hz, 1H), 7.20-7.40
(m, 3H), 7.48-7.56 (m, 6H), 7.97 (d, J=8.14 Hz, 1H), 8.67 (s, 1H),
8.87 (s, 1H); MS (ESI(+)) m/e 375.0 (M+H).sup.+.
Example 331
N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)pheny-
l]urea
The desired product was prepared by substituting
1-isocyanato-3-(trifluoromethyl)benzene for
1-isocyanato-3-methylbenzene, in example 1B and Example 327B for
example 1A in example 1C. In addition
PdCl.sub.2.dppf.CH.sub.2Cl.sub.2 was used in place of
Pd(PPh.sub.3).sub.4. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta.
ppm 5.45 (s, 2H), 7.17 (d, J=7.12 Hz, 1H), 7.25-7.45 (m, 3H),
7.50-7.60 (m, 5H), 7.97 (d, J=7.46 Hz, 1H), 8.04 (s, 1H), 9.02 (s,
1H), 9.14 (s, 1H); MS (ESI(+)) m/e 429 (M+H).sup.+.
Example 332
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5-met-
hylphenyl)urea
Example 332A
2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine
The desired product was prepared by substituting
4-bromo-2-fluoro-phenylamine for Example 149A in Example 149B.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 3.32 (s, 12H) 5.56
(s, 2H) 6.72 (dd, J=8.82, 7.80 Hz, 1H) 7.13 (m, 1H) 7.18 (dd,
J=7.97, 1.19 Hz, 1H).
Example 332B
N-(2-fluoro-5-methylphenyl)-N'-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)phenyl]urea
The desired product was prepared by substituting Example 332A for
4-bromo-2-ethylaniline in Example 149A. MS (ESI(+)) m/e 389
(M+H).sup.+.
Example 332C
7-fluoro-4-iodo-1H-indazol-3-amine
The desired product was prepared by substituting Example 26A for
Example 15E in Example 15F. MS (ESI(+)) m/e 278 (M+H).sup.+.
Example 332D
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N'-(2-fluoro-5-met-
hylphenyl)urea
The desired product was prepared by substituting Example 332B and
Example 332C for Example 1B and Example 1A, respectively, in
Example 1C. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.28
(s, 3H), 6.77-6.81 (m, 2H), 7.09-7.17 (m, 2H), 7.24 (dd, J=8.48,
2.03 Hz, 1H), 7.36 (dd, J=12.21, 2.03 Hz, 1H), 8.03 (dd, J=7.97,
2.20 Hz, 1H), 8.31 (t, J=8.48 Hz, 1H), 9.03 (d, J=2.37 Hz, 1H),
9.15 (d, J=2.37 Hz, 1H); MS (ESI(+) m/e 412 (M+H).sup.+.
Example 333
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl-
)urea
Example 333A
N-(3-chlorophenyl)-N'-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl]urea
The desired product was prepared by substituting Example 332A and
1-chloro-3-isocyanato-benzene for 4-bromo-2-ethylaniline and
1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example
149A. MS (ESI(+)) m/e 391 (M+H).sup.+.
Example 333B
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N'-(3-chlorophenyl-
)urea
The desired product was prepared by substituting Example 333A and
Example 332C for Example 1B and Example 1A, respectively, in
Example 1C. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 6.79
(dd, J=7.80, 4.07 Hz, 1H), 7.03-7.07 (m, 1H), 7.14 (dd, J=11.36,
7.97 Hz, 1H), 7.24-7.39 (m, 4H), 7.75 (t, J=2.03 Hz, 1H), 8.25 (t,
J=8.48 Hz, 1H), 8.73 (d, J=2.37 Hz, 1H), 9.31 (s, 1H); MS (ESI(+)
m/e 414 (M+H).sup.+.
Example 334
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}-2-fluor-
ophenyl)-N'-(2-fluoro-5-methylphenyl)urea
Example 334A
2-fluoro-6-iodo-3-[(1-methylpiperidin-4-yl)methoxy]benzonitrile
The desired product was prepared by substituting
1-methyl-4-piperidinemethanol for 2-(4-morpholinyl)ethanol in
Example 75A. MS (ESI(+)) m/e 375 (M+H).sup.+.
Example 334B
4-iodo-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-3-amine
The desired product was prepared by substituting Example 334A for
Example 15E in Example 15F. MS (ESI(+)) m/e 387 (M+H).sup.+.
Example 334C
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}-2-fluor-
ophenyl)-N'-(2-fluoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 334B and
Example 5A for Example 1A and Example 1B in Example 1C. .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 1.42-1.58 (m, 2H), 2.08-2.18
(m, 3H), 2.28 (s, 3H), 2.79 (d, J=4.75 Hz, 3H), 2.91-3.11 (m, 2H),
3.51 (d, J=12.21 Hz, 2H), 4.03 (d, J=6.44 Hz, 2H), 6.71 (d, J=7.80
Hz, 1H), 6.81-6.83 (m, 2H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.36
(d, J=8.48 Hz, 2H), 7.57 (d, J=8.81 Hz, 2H), 8.00 (dd, J=7.97, 2.20
Hz, 1H), 8.53 (d, J=2.71 Hz, 1H), 9.19 (s, 1H); MS (ESI(+) m/e 503
(M+H).sup.+.
Example 335
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)--
N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 334B for
Example 1A in Example 1C. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 1.41-1.53 (m, 2H), 2.07-2.18 (m, 3H), 2.29 (s, 3H),
2.79 (d, J=4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51 (d, J=12.55 Hz,
2H), 4.03 (d, J=6.44 Hz, 2H), 6.71 (d, J=7.46 Hz, 1H), 6.81 (m,
2H), 7.16 (m, 1H), 7.25 (d, J=8.14 Hz, 1H), 7.32 (s, 1H), 7.34 (d,
J=8.48 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 8.69 (s, 1H), 8.83 (s,
1H); MS (ESI(+) m/e 485 (M+H).sup.+.
Example 336
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)--
N'-(3-chlorophenyl)urea
The desired product was prepared by substituting Example 334B and
1-chloro-3-isocyanatobenzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.41-1.53 (m, 2H),
2.07-2.18 (m, 3H), 2.79 (d, J=4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51
(d, J=12.55 Hz, 2H), 4.03 (d, J=6.44 Hz, 2H), 6.72 (d, J=7.80 Hz,
1H), 6.82 (d, J=7.80 Hz, 1H), 7.01-7.04 (m, 1H), 7.30-7.32 (m, 2H),
7.36 (d, J=8.48 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 7.74 (m, 1H),
8.98 (s, 1H), 9.04 (s, 1H); MS (ESI(+) m/e 505 (M+H).sup.+.
Example 337
N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)--
N'-(4-fluoro-3-methylphenyl)urea
The desired product was prepared by substituting Example 334B and
1-fluoro-2-methyl-4-isocyanatobenzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 1.41-1.53 (m, 2H),
2.07-2.18 (m, 3H), 2.22 (s, 3H) 2.79 (d, J=4.75 Hz, 3H), 2.92-3.05
(m, 2H), 3.51 (d, J=12.55 Hz, 2H), 4.03 (d, J=6.44 Hz, 2H), 6.72
(d, J=7.46 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H), 7.05 (t, J=9.16 Hz,
1H), 7.25-7.40 (m, 2H), 7.34 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.82
Hz, 2H), 8.73 (s, 1H), 8.85 (s, 1H); MS (ESI(+) m/e 503
(M+H).sup.+.
Example 338
N-{-4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chl-
orophenyl)urea
Example 338A
2-fluoro-6-iodo-3-(3-pyridin-3-ylpropoxy)benzonitrile
The desired product was prepared by 3-pyridinepropanol for
2-(4-morpholinyl)ethanol in Example 75A. MS (ESI(+)) m/e 383
(M+H).sup.+.
Example 338B
4-iodo-7-(3-pyridin-3-ylpropoxy)-1H-indazol-3-amine
The desired product was prepared by substituting Example 338A for
Example 15E in Example 15F. MS (ESI(+)) m/e 395 (M+H).sup.+.
Example 338C
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlo-
rophenyl)urea
The desired product was prepared by substituting Example 338B and
1-chloro-3-isocyanatobenzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13-2.22 (m, 2H),
3.05 (t, J=7.12 Hz, 2H), 4.16 (t, J=5.93 Hz, 2H), 6.73 (d, J=7.80
Hz, 1H), 6.81 (d, J=7.80 Hz, 1H), 7.01-7.04 (m, 1H), 7.27-7.32 (m,
2H), 7.37 (d, J=8.81 Hz, 2H), 7.58 (d, J=8.81 Hz, 2H), 7.74 (t,
J=2.03 Hz, 1H), 7.83 (dd, J=7.80, 5.42 Hz, 1H), 8.32 (d, J=7.80 Hz,
1H), 8.69 (d, J=4.07 Hz, 1H), 8.77 (d, J=2.03 Hz, 1H), 8.97 (s,
1H), 9.03 (s, 1H); MS (ESI(+) m/e 513 (M+H).sup.+.
Example 339
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-meth-
ylphenyl)urea
The desired product was prepared by substituting Example 338B for
Example 1A in Example 1C. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.15-2.22 (m, 2H), 2.29 (s, 3H), 3.05 (t, J=7.12 Hz,
2H), 4.16 (t, J=5.93 Hz, 2H), 6.72 (d, J=7.80 Hz, 1H), 6.79-6.82
(m, 2H), 7.16 (m, 1H), 7.25 (m, 1H), 7.32 (s, 1H), 7.35 (d, J=8.81
Hz, 2H), 7.57 (d, J=8.81 Hz, 2H), 7.83 (dd, J=7.80, 5.42 Hz, 1H),
8.31 (d, J=8.14 Hz, 1H), 8.69 (m, 2H), 8.77 (d, J=1.69 Hz, 1H),
8.82 (s, 1H); MS (ESI(+) m/e 493 (M+H).sup.+.
Example 340
N-{-4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[4-flu-
oro-3-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 338B and
1-fluoro-4-isocyanato).sup.-2-(trifluoromethyl)benzene for Example
1A and 1-isocyanato-3-methylbenzene, respectively, in Examples
1B-C. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.07-2.19 (m,
2H), 3.05 (t, J=7.12 Hz, 2H), 4.15 (t, J=5.93 Hz, 2H), 6.71 (d,
J=7.80 Hz, 1H), 6.80 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.82 Hz, 2H),
7.45 (t, J=9.16 Hz, 1H), 7.58 (d, J=8.48 Hz, 2H), 7.66 (m, 1H),
7.78 (dd, J=7.80, 5.42 Hz, 1H), 8.04 (dd, J=6.78, 2.71 Hz, 1H),
8.25 (d, J=8.14 Hz, 1H), 8.66 (d, J=4.41 Hz, 1H), 8.74 (d, J=1.70
Hz, 1H), 9.00 (s, 1H), 9.16 (s, 1H); MS (ESI(+) m/e 565
(M+H).sup.+.
Example 341
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(4-fluo-
ro-3-methylphenyl)urea
The desired product was prepared by substituting Example 338B and
1-fluoro-4-isocyanato-2-methylbenzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.15-2.22 (m, 2H),
2.22 (s, 3H), 3.05 (t, J=7.12 Hz, 2H), 4.15 (t, J=6.10 Hz, 2H),
6.72 (d, J=7.80 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H), 7.05 (t, J=9.16
Hz, 1H), 7.19-7.40 (m, 4H), 7.56 (d, J=8.48 Hz, 2H), 7.82 (dd,
J=7.97, 5.26 Hz, 1H), 8.30 (d, J=7.12 Hz, 1H), 8.69 (dd, J=5.43,
1.36 Hz, 1H), 8.73 (s, 1H), 8.76 (d, J=1.70 Hz, 1H), 8.85 (s, 1H);
MS (ESI(+) m/e 511 (M+H).sup.+.
Example 342
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlo-
ro-4-fluorophenyl)urea
The desired product was prepared by substituting Example 338B and
1-fluoro-2-chloro-4-isocyanatobenzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13-2.22 (m, 2H),
3.05 (t, J=7.12 Hz, 2H), 4.15 (t, J=5.93 Hz, 2H), 6.71 (d, J=7.80
Hz, 1H), 6.80 (d, J=7.80 Hz, 1H), 7.33-7.38 (m, 4H), 7.57 (d,
J=8.48 Hz, 2H), 7.77-7.84 (m, 2H), 8.27 (d, J=7.80 Hz, 1H), 8.67
(dd, J=5.42, 1.36 Hz, 1H), 8.75 (d, J=1.70 Hz, 1H), 8.97 (s, 1H),
9.01 (s, 1H); MS (ESI(+) m/e 531 (M+H).sup.+.
Example 343
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-[3-(tri-
fluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 338B and
1-isocyanato-3-(trifluoromethyl)benzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13-2.22 (m, 2H),
3.05 (t, J=7.12 Hz, 2H), 4.15 (t, J=6.10 Hz, 2H), 6.72 (d, J=7.80
Hz, 1H), 6.81 (m, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.37 (d, J=8.48 Hz,
2H), 7.53 (t, J=7.97 Hz, 1H), 7.60 (m, 3H), 7.81 (dd, J=8.14, 5.42
Hz, 1H), 8.05 (s, 1H), 8.28 (d, J=8.14 Hz, 1H), 8.68 (dd, J=5.26,
1.19 Hz, 1H), 8.76 (d, J=1.70 Hz, 1H), 9.01 (s, 1H), 9.19 (s, 1H);
MS (ESI(+) m/e 547 (M+H).sup.+.
Example 344
N-{-4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(2-flu-
oro-5-methylphenyl)urea
Example 344A
2-fluoro-6-iodo-3-(3-pyridin-4-ylpropoxy)benzonitrile
The desired product was prepared by 4-pyridinepropanol for
2-(4-morpholinyl)ethanol in Example 75A. MS (ESI(+) ink 382.9
(M+H).sup.+.
Example 344B
4-iodo-7-(3-pyridin-4-ylpropoxy)-1H-indazol-3-amine
The desired product was prepared by substituting Example 344A for
Example 15E in Example 15F. MS (ESI(+) m/e 395 (M+H).sup.+.
Example 344C
N-{-4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(2-flu-
oro-5-methylphenyl)urea
The desired product was prepared by substituting Example 344B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.09-2.15 (m, 2H),
2.28 (s, 3H), 2.90 (t, J=7.12 Hz, 2H), 4.13 (t, J=6.10 Hz, 2H),
4.32 (s, 2H), 6.67 (d, J=7.80 Hz, 1H), 6.75 (d, J=7.80 Hz, 1H),
6.78-6.82 (m, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.31 (d, J=6.10
Hz, 2H), 7.36 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.01
(dd, J=7.97, 2.20 Hz, 1H), 8.47 (d, J=5.76 Hz, 2H), 8.53 (d, J=2.71
Hz, 1H), 9.18 (s, 1H), 11.90 (s, 1H); MS (ESI(+) m/e 511
(M+H).sup.+.
Example 345
N-{-4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-met-
hylphenyl)urea
The desired product was prepared by substituting Example 344B for
Example 1A in Example 1C. .sup.1H NMR (300 MHz, DMSO-D.sub.6)
.delta. ppm 2.07-2.16 (m, 2H), 2.29 (s, 3H), 2.90 (m, 2H), 4.13 (t,
J=5.93 Hz, 2H), 4.32 (s, 2H), 6.67 (d, J=7.46 Hz, 1H), 6.75 (d,
J=7.80 Hz, 1H), 6.80 (d, J=7.12 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H),
7.25 (d, J=8.14 Hz, 1H), 7.31 (dd, J=4.07, 1.70 Hz, 3H), 7.35 (d,
J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.47 (d, J=6.10 Hz, 2H),
8.64 (s, 1H), 8.77 (s, 1H), 11.90 (s, 1H); MS (ESI(+) m/e 493
(M+H).sup.+.
Example 346
N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(3-chlo-
rophenyl)urea
The desired product was prepared by substituting Example 344B and
1-chloro-3-isocyanatobenzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.13 (m, 2H), 4.13
(t, J=6.10 Hz, 2H), 4.32 (s, 2H), 6.67 (d, J=7.80 Hz, 1H), 6.75 (m,
1H), 7.02 (m, 1H), 7.31 (m, J=6.10, 2.03 Hz, 5H), 7.36 (d, J=8.81
Hz, 2H), 7.56 (m, J=8.48 Hz, 3H), 7.73 (s, 1H), 8.47 (m, 2H), 8.90
(s, 1H), 8.97 (s, 1H), 11.90 (s, 1H); MS (ESI(+) m/e 513
(M+H).sup.+.
Example 347
N-[4-(3-amino-1H-indazol-4-yl)-2-(methoxymethoxy)phenyl]-N'-(2-fluoro-5-me-
thylphenyl)urea
Example 347A
N-(4-bromo-2-hydroxyphenyl)-N'-(2-fluoro-5-methylphenyl)urea
The desired product was prepared by substituting
2-Amino-5-bromo-phenol for 4-bromo-2-ethylaniline in example 149A.
MS (ESI(+)) m/e 339 and 341 (M+H).sup.+.
Example 347B
N-[4-bromo-2-(methoxymethoxy)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
A solution of example 347A (68 mg, 0.2 mmol) in acetone (2 mL) was
treated with K2CO3 (41 mg, 0.3 mmol) and MOM-Cl (0.023 mL, 0.3
mmol), stirred at reflux for 2 h, then allowed to cool to room
temperature and treated with water. The resulting suspension was
filtered and the filter cake was dried to give 58 mg of example
347B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 2.27 (s, 3H)
3.45 (s, 3H) 5.32 (s, 2H) 6.78-6.83 (m, 1H) 7.12-7.15 (m, 2H) 7.29
(d, J=2.37 Hz, 1H) 7.98 (dd, J=7.97, 1.86 Hz, 1H) 8.13 (d, J=8.82
Hz, 1H) 8.82 (s, 1H) 9.22 (d, J=1.70 Hz, 1H).
Example 347C
N-[4-(3-amino-1H-indazol-4-yl)-2-(methoxymethoxy)phenyl]-N'-(2-fluoro-5-me-
thylphenyl)urea
The desired product was prepared substituting example 347B for
example 44A in example 44B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) d
ppm 2.28 (s, 3H) 3.47 (s, 3H) 4.42 (s, 2H) 5.37 (s, 2H) 6.78-6.83
(m, 2H) 7.08 (dd, J=8.3, 1.9 Hz, 1H) 7.11 (dd, J=11.4, 8.3 Hz, 1H)
7.24 (d, J=2.0 Hz, 1H) 7.26 (s, 1H) 7.27 (d, J=2.7 Hz, 1H) 8.04
(dd, J=8.1, 2.0 Hz, 1H) 8.29 (d, J=8.5 Hz, 1H) 8.89 (s, 1H) 9.26
(d, J=1.7 Hz, 1H) 11.72 (s, 1H); MS (ESI(+)) m/e 436.2
(M+H).sup.+.
Example 348
N-[4-(3-amino-1H-indazol-4-yl)-2-hydroxyphenyl]-N'-(2-fluoro-5-methylpheny-
l)urea
Example 348A
N-(4-bromo-2-tetrahydro-2H-pyran-2-ylphenyl)-N'-(2-fluoro-5-methylphenyl)u-
rea
A solution of example 347A (150 mg, 0.44 mmol) and dihydropyran
(0.24 mL, 2.4 mmol) in CH.sub.2Cl.sub.2 (2 mL) was treated with
TsOH (1 mg) stirred at room temperature for 1 h then partitioned
between EtOAc and sat. aq. NaHCO3 solution. The organic extract was
washed with brine, dried (MgSO4), concentrated and purified via
silica gel chromatography eluting with 20% EtOAc-hexanes to give
190 mg of 348A.
Example 348B
N-[4-(3-amino-1H-indazol-4-yl)-2-hydroxyphenyl]-N'-(2-fluoro-5-methylpheny-
l)urea
The desired product was prepared by substituting example 348A (190
mg, 0.4 mmol) for 44A in example 44B, then dissolving the crude
product in methanol treating with one drop of 1N HCl and stirring
at r.t for 12 h. Purification via silica gel chromatography eluting
with 5% methanol-methylene chloride gave 14 mg of 348B. .sup.1H NMR
(500 MHz, DMSO-D.sub.6) d ppm 2.28 (s, 3H) 6.77-6.81 (m, 2H) 6.85
(dd, J=8.4, 1.9 Hz, 1H) 6.94 (d, J=2.2 Hz, 1H) 7.09 (dd, J=11.2,
8.4 Hz, 1H) 7.24-7.29 (m, 2H) 8.02 (dd, J=7.8, 1.3 Hz, 1H) 8.17 (d,
J=8.4 Hz, 1H) 8.81 (s, 1H) 9.19 (d, J=1.9 Hz, 1H) 10.14 (s, 1H)
11.74 (s, 1H); MS (ESI(+)) m/e 391.7 (M+H).sup.+.
Example 349
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(hydroxymethyl)phenyl-
]urea
Example 349A
N-(4-bromophenyl)-N'-[2-fluoro-5-(hydroxymethyl)phenyl]urea
A solution of (3-amino-4-fluoro-phenyl).sup.-methanol (0.61 g, 4.3
mmol) in CH.sub.2Cl.sub.2 (20 mL) was treated with
1-isocyanato-4-bromobenzene (0.85 g, 4.3 mmol) stirred at room
temperature overnight resulting in a thick suspension which was
filtered to give 1.43 g of 349 as a off white solid. MS (ESI(-))
m/e 336.9, 338.9 (M-H).sup.+.
Example 349B
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(hydroxymethyl)phenyl-
]urea
The desired product was prepared by substituting example 349A for
149A in examples 149B-C. .sup.1H NMR (300 MHz, DMSO-D.sub.6) d ppm
4.33 (s, 2H) 4.46 (d, J=5.8 Hz, 2H) 5.22 (t, J=5.8 Hz, 1H) 6.79
(dd, J=5.4, 2.4 Hz, 1H) 6.95 (ddd, J=8.1, 4.8, 2.0 Hz, 1H)
7.11-7.30 (m, 3H) 7.41 (d, J=8.5 Hz, 2H) 7.60 (d, J=8.5 Hz, 2H)
8.16 (dd, J=7.8, 2.0 Hz, 1H) 8.58 (d, J=2.4 Hz, 1H) 9.21 (s, 1H)
11.71 (s, 1H); MS (ESI(+)) m/e 392.0 (M+H).sup.+.
Example 350
N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)-
phenyl]urea
Example 350A
4-(4-aminophenyl)-7-thien-3-yl-1H-indazol-3-amine
The desired product was prepared substituting thiophene-3-boronic
acid for pyridine-3-boronic acid in examples 243D-E, then following
the procedure of example 352B. Rf=0.24 (EtOAc).
Example 350B
N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)-
phenyl]urea
The desired product was prepared by substituting Example 350A and
1-isocyanato-3-trifluoromethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. NMR
(300 MHz, DMSO-D.sub.6) d ppm 6.92 (d, J=7.1 Hz, 1H) 7.33 (d, J=7.5
Hz, 1H) 7.44 (d, J=8.8 Hz, 2H) 7.48-7.68 (m, 6H) 7.73 (dd, J=4.8,
2.7 Hz, 1H) 7.96 (d, J=2.4 Hz, 1H) 8.05 (s, 1H) 9.01 (s, 1H) 9.15
(s, 1H) 11.96 (s, 1H); MS (ESI(+)) m/e 494.0 (M+H).sup.+.
Example 351
N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylph-
enyl)urea
The desired product was prepared by substituting Example 350A and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) d ppm 2.29 (s, 3H) 6.79-6.84 (m, 1H)
6.89 (d, J=7.5 Hz, 1H) 7.12 (dd, J=11.4, 8.3 Hz, 1H) 7.44 (d, J=8.5
Hz, 2H) 7.54 (d, J=7.1 Hz, 1H) 7.57-7.64 (m, 3H) 7.72 (dd, J=4.9,
2.9 Hz, 1H) 7.95 (s, 1H) 8.02 (d, J=6.8 Hz, 1H) 8.55 (d, J=2.0 Hz,
1H) 9.23 (s, 1H) 11.84 (s, 1H); MS (ESI(+)) m/e 458.1
(M+H).sup.+.
Example 352
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methyl-
phenyl)urea
Example 352A
4-(4-nitrophenyl)-7-pyridin-4-yl-1H-indazol-3-amine
The desired product was prepared by substituting pyridine-4-boronic
acid for pyridine-3-boronic acid in examples 243D-E. Unlike example
243E only a small amount (ca. 20%) of the reduced product 352A was
obtained. MS (ESI(+)) m/e 332 (M+H).sup.+.
Example 352B
4-(4-aminophenyl)-7-pyridin-4-yl-1H-indazol-3-amine
A mixture of 352A (370 mg, 1.1 mmol), iron (374 mg) and NH4Cl (60
mg, 1.1 mmol) in ethanol (20 mL), THF (10 mL) and water (4 mL) was
heated at reflux for 5 h, diluted with THF (20 mL), filtered
through a pad of celite, washing with ethanol. The filtrate was
concentrated and the residue was triturated from water to give 313
mg of 352A as a light yellow solid. MS (ESI(+)) m/e 302
(M+H).sup.+.
Example 352C
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methyl-
phenyl)urea
The desired product was prepared by substituting Example 352B and
1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) d ppm 2.23 (d, J=2.0 Hz, 3H) 7.02 (d,
J=7.5 Hz, 1H) 7.06 (t, J=9.2 Hz, 1H) 7.29 (ddd, J=8.7, 4.3, 2.9 Hz,
1H) 7.39 (dd, J=7.1, 2.4 Hz, 1H) 7.46 (d, J=8.8 Hz, 2H) 7.64 (d,
J=8.8 Hz, 2H) 7.72 (d, J=7.5 Hz, 1H) 8.22 (d, J=3.7 Hz, 2H) 8.78
(s, 1H) 8.85-8.92 (m, 2H) 8.96 (s, 1H); MS (ESI(+)) m/e 453.3
(M+H).sup.+.
Example 353
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethy-
l)phenyl]urea
The desired product was prepared by substituting Example 352B and
1-isocyanato-3-trifluoromethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) d ppm 7.02 (d, J=7.1 Hz, 1H) 7.33 (d,
J=7.5 Hz, 1H) 7.48 (d, J=8.5 Hz, 2H) 7.53 (t, J=8.0 Hz, 1H) 7.62
(d, J=8.5 Hz, 1H) 7.67 (d, J=8.5 Hz, 2H) 7.71 (d, J=7.8 Hz, 1H)
8.05 (s, 1H) 8.19 (d, J=2.4 Hz, 2H) 8.87 (d, J=2.4 Hz, 2H) 9.11 (s,
1H) 9.23 (s, 1H); MS (ESI(+)) m/e 489.1 (M+H).sup.+.
Example 354
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)ur-
ea
The desired product was prepared by substituting Example 352B and
1-chloro-3-isocyanatobenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) d ppm 7.00-7.05 (m, 2H) 7.29-7.33 (m,
2H) 7.47 (d, J=8.8 Hz, 2H) 7.65 (d, J=8.8 Hz, 2H) 7.70 (d, J=7.5
Hz, 1H) 7.75 (dd, J=2.5, 1.2 Hz, 1H) 8.17 (d, J=3.7 Hz, 2H) 8.86
(d, J=3.7 Hz, 2H) 9.08 (app. s, 2H); MS (ESI(+)) m/e 455.2
(M+H).sup.+.
Example 355
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methyl-
phenyl)urea
The desired product was prepared by substituting Example 352B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) d ppm 2.29 (s, 3H) 6.80-6.85 (m, 1H)
7.01 (d, J=7.5 Hz, 1H) 7.12 (dd, J=11.4, 8.3 Hz, 1H) 7.47 (d, J=8.8
Hz, 2H) 7.64 (d, J=8.8 Hz, 2H) 7.69 (d, J=7.5 Hz, 1H) 8.01 (dd,
J=8.0, 1.9 Hz, 1H) 8.14-8.19 (m, 2H) 8.57 (d, J=2.7 Hz, 1H)
8.82-8.89 (m, 2H) 9.28 (s, 1H); MS (ESI(+)) m/e 453.3
(M+H).sup.+.
Example 356
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifl-
uoromethyl)phenyl]urea
The desired product was prepared by substituting Example 352B and
1-fluoro-4-isocyanato-2-trifluoromethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) d ppm 4.45 (s, 2H) 6.95 (d, J=7.5 Hz,
1H) 7.42-7.47 (m, 1H) 7.45 (d, J=8.5 Hz, 2H) 7.50 (d, J=7.5 Hz, 1H)
7.64 (d, J=8.5 Hz, 2H) 7.64-7.69 (m, 1H) 7.71 (d, J=6.1 Hz, 2 H)
8.03 (dd, J=6.6, 2.6 Hz, 1H) 8.68 (d, J=6.1 Hz, 2H) 8.99 (s, 1H)
9.11 (s, 1H) 11.98 (s, 1 H); MS (ESI(+)) m/e 507.2 (M+H).sup.+.
Example 357
N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-5-(trifl-
uoromethyl)phenyl]urea
The desired product was prepared by substituting Example 352B and
1-fluoro-2-isocyanato-4-trifluoromethylbenzene for Example 15G and
1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.
Additionally, DMF was used in place of CH.sub.2Cl.sub.2. .sup.1H
NMR (300 MHz, DMSO-D.sub.6) d ppm 7.01 (d, J=7.5 Hz, 1H) 7.42-7.49
(m, 3H) 7.65-7.71 (m, 4H) 8.04 (dd, J=6.4, 2.7 Hz, 1H) 8.14-8.21
(m, 2H) 8.82-8.90 (m, 2H) 9.12 (s, 1H) 9.23 (s, 1H); MS (ESI(+))
m/e 507.7 (M+H).sup.+.
Example 358
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
Example 358A
5-fluoro-4-iodo-1H-indazol-3-amine
The desired product was prepared by substituting
2,5-difluoro-benzonitrile for example 243A in example 243B, then
substituting the product for 2-fluoro-6-iodo-benzonitrile in
example 1A. MS (ESI(+) m/e 278 (M+H).sup.+.
Example 358B
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-bromophenyl)urea
The desired product was prepared by substituting
1-bromo-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene and
Example 358B for 1A, respectively and in Examples 1B-C and
purifying as in example 3. .sup.1H NMR (300 MHz, DMSO-D.sub.6) d
ppm 7.15-7.38 (m, 7H) 7.61 (d, J=8.8 Hz, 2H) 7.88 (t, J=1.9 Hz, 1H)
8.95 (s, 1H) 8.95 (s, 1H) 11.82 (s, 1H); MS (ESI(+)) m/e 439.9,
441.9 (M+H).sup.+.
Example 359
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-methylphenyl)urea
The desired product was prepared by substituting Example 358B for
1A in Examples 1C and purifying as in example 3. .sup.1H NMR (300
MHz, DMSO-D.sub.6) d ppm 2.29 (s, 3H) 4.19 (s, 2H) 6.80 (d, J=7.5
Hz, 1H) 7.14-7.30 (m, 4H) 7.32 (s, 1H) 7.35 (d, J=8.5 Hz, 2H) 7.61
(d, J=8.5 Hz, 2H) 8.65 (s, 1H) 8.83 (s, 1H) 11.74 (s, 1H); MS
(ESI(+)) m/e 376.1 (M+H).sup.+.
Example 360
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-phenylurea
The desired product was prepared by substituting
1-isocyanatobenzene for 1-isocyanato-3-methylbenzene and Example
358B for 1A, respectively and in Examples 1B-C and purifying as in
example 3. .sup.1H NMR (300 MHz, DMSO-D.sub.6) d ppm 6.98 (t, J=7.3
Hz, 1H) 7.21 (t, J=9.3 Hz, 1H) 7.27-7.32 (m, 3H) 7.36 (d, J=8.1 Hz,
2H) 7.48 (d, J=7.8 Hz, 2H) 7.61 (d, J=8.5 Hz, 2H) 8.74 (s, 1H) 8.86
(s, 1H) 11.81 (s, 1H).
Example 361
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-[2-fluoro-3-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting
1-fluoro-2-isocyanato-4-trifluoromethylbenzene for
1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively
and in Examples 1B-C. .sup.1H NMR (300 MHz, DMSO-D.sub.6) d ppm
7.21 (t, J=9.2 Hz, 1H) 7.29 (dd, J=9.2, 4.1 Hz, 1H) 7.37-3.40 (m,
4H) 7.63 (d, J=8.5 Hz, 2H) 8.45-8.50 (m, 1H) 8.90 (d, J=2.4 Hz, 1H)
9.32 (s, 1H) 11.81 (br. s, 1H); MS (ESI(+)) m/e 448.1
(M+H).sup.+.
Example 362
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
The desired product was prepared by substituting Example 358B and
5A for 1A and 1B, respectively in Examples 1C and purifying as in
example 3. .sup.1H NMR (300 MHz, DMSO-D.sub.6) d ppm 2.28 (s, 3H)
6.82 (ddd, J=8.5, 4.8, 2.0 Hz, 1H) 7.12 (dd, J=11.5, 8.1 Hz, 1H)
7.25 (t, J=9.3 Hz, 1H) 7.33 (dd, J=9.2, 4.1 Hz, 1H) 7.38 (d, J=8.5
Hz, 2H) 7.62 (d, J=8.5 Hz, 2H) 8.01 (dd, J=7.8, 2.0 Hz, 1H) 8.55
(d, J=2.4 Hz, 1H) 9.26 (s, 1H) 12.01 (br. s, 1H); MS (ESI(+)) m/e
394.0 (M+H).sup.+.
Example 363
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-[3-(trifluoromethyl)phen-
yl]urea
The desired product was prepared by substituting
1-isocyanato-3-trifluoromethylbenzene for
1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively
in Examples 1B-C and purifying as in example 3. .sup.1H NMR (300
MHz, DMSO-D.sub.6) d ppm 7.22 (t, J=9.5 Hz, 1H) 7.28-7.34 (m, 2H)
7.38 (d, J=8.1 Hz, 2H) 7.53 (t, J=8.0 Hz, 1H) 7.59-7.65 (m, 3H)
8.04 (s, 1H) 9.01 (s, 1H) 9.14 (s, 1H) 11.85 (br. s, 1H); MS
(ESI(+)) m/e 430.0 (M+H).sup.+.
Example 364
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-[4-fluoro-3-(trifluorome-
thyl)phenyl]urea
The desired product was prepared by substituting
1-fluoro-4-isocyanato-3-trifluoromethylbenzene for
1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively
in Examples 1B-C and purifying as in example 3. .sup.1H NMR. (300
MHz, DMSO-D.sub.6) d ppm 7.23 (t, J=9.5 Hz, 1H) 7.32 (dd, J=9.2,
4.1 Hz, 1H) 7.38 (d, J=8.1 Hz, 2H) 7.45 (t, J=9.5 Hz, 1H) 7.66 (m,
3H) 8.03 (dd, J=6.4, 2.7 Hz, 1H) 9.04 (s, 1H) 9.15 (s, 1H) 11.94
(br. s, 1H); MS (ESI(+)) m/e 448.0 (M+H).sup.+.
Example 365
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-chlorophenyl)urea
The desired product was prepared by substituting
1-chloro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene and
Example 358B for 1A, respectively in Examples 1B-C and purifying as
in example 3. .sup.1H NMR (300 MHz, DMSO-D.sub.6) d ppm 7.02-7.05
(m, 1H) 7.25 (t, J=9.5 Hz, 1H) 7.29-7.35 (m, 3H) 7.38 (d, J=8.5 Hz,
2H) 7.62 (d, J=8.5 Hz, 2H) 7.73-7.75 (m, 1H) 9.00 (s, 1H) 9.01 (s,
1H) 12.01 (br. s, 1H); MS (ESI(+)) m/e 396.0 (M+H).sup.+.
Example 366
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(4-fluoro-3-methylphenyl-
)urea
The desired product was prepared by substituting
1-fluoro-4-isocyanato-3-methylbenzene for
1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively
in Examples 1B-C and purifying as in example 3. .sup.1H NMR (300
MHz, DMSO-D.sub.6) d ppm 2.22 (d, J=1.7 Hz, 3 H) 7.06 (t, J=9.2 Hz,
1H) 7.21-7.40 (m, 6H) 7.61 (d, J=8.5 Hz, 2H) 8.71 (s, 1H) 8.88 (s,
1 H) 12.01 (br. s, 1H); MS (ESI(+)) m/e 396.0 (M+H).sup.+.
Example 367
N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N'-(3-chloro-4-fluorophenyl-
)urea
The desired product was prepared by substituting
1-fluoro-2-chloro-4-isocyanatobenzene for
1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively
in Examples 1B-C and purifying as in example 3. .sup.1H NMR (300
MHz, DMSO-D.sub.6) d ppm 7.24 (t, J=9.5 Hz, 1H) 7.30-7.39 (m, 5H)
7.62 (d, J=8.8 Hz, 2H) 7.82-7.85 (m, 1H) 9.00 (s, 1H) 9.01 (s, 1H)
11.99 (br. s, 1H); MS (ESI(+)) m/e 414.0 (M+H).sup.+.
Example 368
N-[4-(3-amino-7-bromo-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)-
urea
The desired product was prepared by substituting
3-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile
and 1-fluoro-2-isocyanato-4-methylbenzene for
1-isocyanato-3-methylbenzene in Examples 1A-C. .sup.1H NMR (300
MHz, DMSO-D.sub.6) d ppm 2.28 (s, 3H) 6.73 (d, J=7.5 Hz, 1H)
6.79-6.84 (m, 1H) 7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.40 (d, J=8.8 Hz,
2 H) 7.51 (d, J=7.80 Hz, 1H) 7.60 (d, J=8.8 Hz, 2H) 8.01 (dd,
J=7.5, 2.0 Hz, 1H) 8.54 (d, J=2.4 Hz, 1H) 9.22 (s, 1H) 12.08 (br.
s, 1H); MS (ESI(+)) m/e 453.9, 455.9 (M+H).sup.+.
Example 369
3-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenz-
oic acid
Example 369A
4-(4-aminophenyl)-1H-indazol-3-amine
The desired product was prepared by substituting
2-fluoro-6-benzonitrile for 15F in example 15G, then substituting
the product for 2-fluoro-6-benzonitrile in example 1A. MS (ESI(+))
m/e 225 (M+H).sup.+.
Example 369B
tert-butyl 3-amino-4-(4-aminophenyl)-1H-indazole-1-carboxylate
A -78 C solution of 369A (100 mg, 0.45 mmol) in THF (6 mL) was
treated with LDA (0.245 mL, 2M solution in heptane, 0.49 mmol),
stirred at -50 for 15 minutes, treated with solid (Boc).sub.2O (98
mg, 0.45 mmol). The reaction was allowed to gradually warm up to
room temperature over 2 h, concentrated in vacuo and purified via
silica gel chromatography eluting first with 75% EtOAc: hexanes
then with 8% methanol: CH.sub.2Cl.sub.2 to give 62 mg of 369B. MS
(ESI(+)) m/e 325 (M+H).sup.+.
Example 369C
methyl
3-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-flu-
orobenzoate
A 0 C solution of 3-Amino-4-fluoro-benzoic acid methyl ester (29
mg, 0.17 mmol) in THF (4 mL) was treated with triethyl amine (0.026
mL) and 4-nitrophenyl chloroformate (38 mg), stirred at 0 C for 45
min, then treated with a solution of example 396B (56 mg, 0.17
mmol) in THF (3 mL) followed by an additional 0.026 mL of Et3N. The
resulting mixture was allowed to warm up to room temperature
slowly, stirred overnight, diluted with water and extracted twice
with EtOAc. The combined organics were washed with brine, dried
(MgSO4), concentrated and purified via silica gel chromatography
eluting with EtOAc to give 98 mg of
3-Amino-4-{4-[3-(2-fluoro-5-methoxycarbonyl-phenyl).sup.-ureido]-phenyl}--
indazole-1-carboxylic acid tert-butyl ester. This compound was
dissolved in CH.sub.2Cl.sub.2 (2 mL), cooled to 0 C, treated with
TFA (1 mL), stirred at 0 for 45 min then at room temperature for 1
h. The reaction was quenched with sat. aq. NaHCO3 adjusting the pH
to 8-9 then extracted with EtOAc (3.times.). The combined organics
were washed with brine, dried (MgSO4), concentrated and purified
via silica gel chromatography eluting with first EtOAc then 12%
methanol:CH.sub.2Cl.sub.2 to give 30 mg of 369C as a white solid.
MS (ESI(+)) m/e 420 (M+H).sup.+.
Example 369D
3-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenz-
oic acid
A solution of 369C (20 mg, 0.05 mmol) in methanol (1 mL) was
treated with a solution of NaOH 911 mg) in water (1 mL), stirred at
reflux for 7 h and concentrated. The residue was diluted with
water, the pH was adjusted to pH of 3 with 1 N HCl, and the
resulting solid was collected via filtration to give 17 mg of 369D.
.sup.1H NMR (300 MHz, DMSO-D.sub.6) d ppm 4.34 (br. s, 2H) 6.79
(dd, J=5.3, 2.5 Hz, 1H) 7.24-7.28 (m, 2H) 7.34-7.43 (m, 3H)
7.60-7.64 (m, 3H) 8.77 (d, J=2.7 Hz, 1H) 8.85 (dd, J=8.1, 2.0 Hz,
1H) 9.27 (s, 1H) 11.72 (br. s, 1H) 13.00 (br. s, 1H).
Example 370
N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea
The desired product was prepared by substituting Example 182A for
1A in Example 5B. MS (ESI(+) Q1MS m/z 376 (M+H).sup.+; .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 2.28 (s, 3H) 6.78-6.84 (m, 1H)
7.11 (dd, J=11.36, 8.31 Hz, 1H) 7.33 (dd, J=8.65, 1.19 Hz, 1H) 7.48
(s, 1H) 7.57 (d, J=8.82 Hz, 2H) 7.67 (d, J=8.82 Hz, 2H) 7.84 (d,
J=8.48 Hz, 1H) 8.00 (dd, J=7.80, 2.37 Hz, 1H) 8.51 (d, J=2.71 Hz,
1H) 9.19 (s, 1H)
Example 371
N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-ind-
azol-7-yl}oxy)ethyl]methanesulfonamide
The desired product was prepared by substituting Example 178A for
Example 15G in Example 15H. MS (ESI(+) Q1MS m/z 499 (M+H).sup.+;
.sup.1H NMR (500 MHz, DMSO-D.sub.6) .delta. ppm 2.99 (s, 3H) 3.44
(q, J=5.61 Hz, 2H) 4.23 (t, J=5.61 Hz, 2H) 6.72 (d, J=7.49 Hz, 1H)
6.79 (td, J=8.58, 2.18 Hz, 1H) 6.83 (d, J=7.80 Hz, 1H) 7.13-7.17
(m, 2H) 7.29-7.34 (m, 1H) 7.37 (d, J=8.42 Hz, 2H) 7.51 (dt,
J=11.93, 2.30 Hz, 1H) 7.57 (d, J=8.73 Hz, 2H) 8.85 (s, 1 H) 8.94
(s, 1H)
Example 372
N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N'-[4-f-
luoro-3-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 248B and
1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G
and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS
(ESI(+) Q1MS m/z 531 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 2.15-2.20 (m, 2H) 2.86 (d, J=5.09 Hz, 6H)
3.34-3.41 (m, 2H) 4.22 (t, J=5.76 Hz, 2H) 6.72 (d, J=7.46 Hz, 1H)
6.81 (d, J=7.80 Hz, 1H) 7.36 (d, J=8.48 Hz, 2H) 7.45 (t, J=9.83 Hz,
1H) 7.58 (d, J=8.48 Hz, 2H) 7.63-7.69 (m, 1H) 8.04 (dd, J=6.44,
2.71 Hz, 1H) 9.02 (s, 1H) 9.18 (s, 1H)
Example 373
N-[4-(1-acetyl-3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
Example 373A
1-acetyl-4-iodo-1H-indazol-3-amine
A solution of example 1A (215 mg, 0.83 mmol), acetic anhydride
(0.086 mL) and 18-crown-6 (438 mg) in CH.sub.2Cl.sub.2 (5 mL) was
stirred at room temperature overnight, then partitioned between
EtOAc and water. The organic extract was dried (MgSO4),
concentrated and purified via silica gel chromatography eluting
with 1 to 1 hexane: EtOAc to give 110 mg of 373A. .sup.1H NMR (300
MHz, DMSO-D.sub.6) .delta. ppm 2.53 (s, 3H) 6.01 (s, 2H) 7.26 (t,
J=7.46 Hz, 1H) 7.77 (d, J=7.46 Hz, 1H) 8.31 (d, J=8.48 Hz, 1H).
Example 373B
N-[4-(1-acetyl-3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
The desired product was prepared by substituting Example 373A for
1A in Example 5B. MS (ESI(-) Q1MS m/z 416 (M-H).sup.-; .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 2.28 (s, 3H) 2.55 (s, 3H) 5.20
(s, 2H) 6.79-6.84 (m, 1H) 7.12 (dd, J=11.53, 8.48 Hz, 1H) 7.18 (d,
J=7.46 Hz, 1H) 7.42 (d, J=8.48 Hz, 2H) 7.57-7.64 (m, 3H) 8.00 (dd,
J=7.63, 1.87 Hz, 1H) 8.29 (d, J=8.14 Hz, 1H) 8.56 (d, J=2.71 Hz,
1H) 9.26 (s, 1H)
Example 374
N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N'-(4-bromo-3-methylphenyl)-
urea
The desired product was prepared as the trifluoroacetate salt by
substituting Example 26B and 1-bromo-4-isocyanato-2-methylbenzene
for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in
Example 15H. MS (ESI(+)): ink 456 (M+H); .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 2.32 (s, 3H) 6.74 (dd, J=7.80, 4.41 Hz,
1H) 7.13 (dd, J=11.19, 7.80 Hz, 1H) 7.27 (dd, J=8.65, 2.54 Hz, 1H)
7.37 (d, J=8.48 Hz, 2H) 7.44-7.49 (m, 2H) 7.58 (d, J=8.48 Hz, 2H)
8.80 (s, 1H) 8.87 (s, 1H).
Example 375
N-[4-(3-amino-1-phenyl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
Example 375A
2-(4-iodo-1-phenyl-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione
A mixture of 162A (940 mg), phenyl boronic acid (590 mg), cupric
acetate (440 mg), triethylamine (0.674 mL) in CH.sub.2Cl.sub.2 (20
mL) was stirred at room temperature overnight, then concentrated.
The residue was purified via silica gel chromatography eluting with
20% EtOAc in hexane to give 770 mg of 375A. MS (ESI(+)) m/e 466.1
(M+H).sup.+.
Example 375B
4-iodo-1-phenyl-1H-indazol-3-amine
The desired product was prepared by substituting 375A for 162B in
example 162C. MS (ESI(+)) m/e 336.1 (M+H).sup.+.
Example 375C
N-[4-(3-amino-1-phenyl-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl-
)urea
The desired product was prepared by substituting Example 375B for
1A in Example 5B. MS (ESI(+) Q1MS m/z 452 (M+H).sup.+; .sup.1H NMR
(300 MHz, DMSO-D.sub.6) .delta. ppm 2.29 (s, 3H) 4.75 (s, 2H) 6.83
(m, 1H) 6.97 (d, J=6.44 Hz, 1H) 7.12 (dd, J=11.53, 8.48 Hz, 1H)
7.26 (t, J=7.29 Hz, 1H) 7.43-7.47 (m, 3H) 7.50-7.55 (m, 2H)
7.61-7.74 (m, 5H) 8.01 (dd, J=7.97, 2.20 Hz, 1H) 8.57 (d, J=2.37
Hz, 1H) 9.26 (s, 1H)
Example 376
N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N'-(2-fluo-
ro-5-methylphenyl)urea
The desired product was prepared by substituting Example 338B and
1-fluoro-2-isocyanato-4-methylbenzene for Example 1A and
1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. MS
(ESI(+) Q1MS m/z 511 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 2.14-2.18 (m, 2H) 2.28 (s, 3H) 3.01 (t,
J=7.4 Hz, 2H) 4.14 (t, J=6.10 Hz, 2H) 6.70 (d, J=7.80 Hz, 1H)
6.77-6.84 (m, 2H) 7.11 (dd, J=11.36, 8.31 Hz, 1H) 7.37 (d, J=8.82
Hz, 2H) 7.56 (d, J=8.48 Hz, 2H) 7.70-7.73 (m, 1H) 8.01 (dd, J=7.97,
2.20 Hz, 1H) 8.17 (d, J=9.49 Hz, 1H) 8.52 (d, J=3.05 Hz, 1H) 8.62
(d, J=5.09 Hz, 1H) 8.70 (s, 1H) 9.17 (s, 1H).
Example 377
N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-phenylurea
The desired product was prepared by substituting Example 182A and
N-phenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-
urea for 1A and 5A respectively, in Example 5B. MS (ESI(+) Q1MS m/z
344 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
5.33 (s, 2H) 6.97 (t, J=7.29 Hz, 1H) 7.19 (dd, J=8.31, 1.19 Hz, 1H)
7.28 (t, J=7.97 Hz, 2H) 7.38 (s, 1H) 7.48 (d, J=7.46 Hz, 2H) 7.59
(m, 4H) 7.72 (d, J=8.48 Hz, 1H) 8.90 (s, 1H) 8.96 (s, 1H) 11.38 (s,
1H)
Example 378
N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N'-[3-(trifluoromethyl)phenyl]urea
The desired product was prepared by substituting Example 182A and
N-(3-trifluoromethylphenyl).sup.-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]urea for 1A and 5A respectively, in Example 5B.
MS (ESI(+) Q1MS m/z 412 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-D.sub.6) .delta. ppm 7.33 (dd, J=7.97, 4.58 Hz, 2H) 7.55-7.58
(m, 3H) 7.58 (d, J=8.82 Hz, 2H) 7.67 (d, J=8.82 Hz, 2H) 7.85 (d,
J=8.48 Hz, 1H) 8.04 (s, 1H) 8.95 (s, 1H) 9.11 (s, 1H).
Example 379
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-thien-3-ylurea
The desired product was prepared by substituting
3-isocyanato-thiophene for 1-isocyanato-3-methylbenzene in Examples
5A-B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm 4.33 (s, 2H)
6.78 (dd, J=5.59, 2.20 Hz, 1H) 7.07 (dd, J=5.09, 1.36 Hz, 1H)
7.24-7.28 (m, 2H) 7.29-7.33 (m, 1H) 7.39 (d, J=8.48 Hz, 2H) 7.45
(dd, J=5.09, 3.39 Hz, 1H) 7.59 (d, J=8.48 Hz, 2H) 8.78 (s, 1H) 8.99
(s, 1H) 11.70 (s, 1H); MS (ESI(+)) m/e 350 (M+H).sup.+.
Example 380
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-cyclopentylurea
The desired product was prepared by substituting
isocyanato-cyclopentane for 1-isocyanato-3-methylbenzene in
Examples 5A-B. .sup.1H NMR (300 MHz, DMSO-D.sub.6) .delta. ppm
1.31-1.45 (m, 2H) 1.47-1.71 (m, 4H) 1.77-1.93 (m, 2H) 3.89-4.00 (m,
1H) 4.31 (s, 2H) 6.21 (d, J=7.12 Hz, 1H) 6.75 (dd, J=5.59, 2.20 Hz,
1H) 7.22-7.27 (m, 2H) 7.32 (d, J=8.48 Hz, 2H) 7.50 (d, J=8.48 Hz,
2H) 8.39 (s, 1H) 11.68 (s, 1H). MS (ESI(+)) m/e 336
(M+H).sup.+.
It will be evident to one skilled in the art that the present
invention is not limited to the foregoing illustrative examples,
and that it can be embodied in other specific forms without
departing from the essential attributes thereof. It is therefore
desired that the examples be considered in all respects as
illustrative and not restrictive, reference being made to the
appended claims, rather than to the foregoing examples, and all
changes which come within the meaning and range of equivalency of
the claims are therefore intended to be embraced therein.
* * * * *